TW202003492A - Substituted 4-aminoisoindoline-1,3-dione compounds, compositions thereof, and methods of treatment therewith - Google Patents

Abstract

Provided herein are 4-aminoisoindoline-1,3-dione compounds having the following structure:, wherein R, Ring A, and n are as defined herein, compositions comprising an effective amount of a 4-aminoisoindoline-1,3-dione compound, and methods for treating or preventing disorders.

Description

Substituted 4-aminoisoindoline-1,3-dione compound, its composition, and method of treatment

Provided herein are 4-aminoisoindoline-1,3-dione compounds, compositions containing effective amounts of these compounds, and methods for treating or preventing diffuse large B-cell lymphoma (DLBCL), which The method includes administering an effective amount of 4-aminoisoindoline-1,3-dione compound to an individual in need.

The characteristics of cancer are mainly the increase in the number of abnormal cells originating from a given normal tissue, the invasion of these abnormal cells into adjacent tissues, or the spread of malignant cells to regional lymph nodes and metastases via lymph or blood. Clinical data and molecular biology studies indicate that cancer is a multi-step process that begins with small precancerous changes that can evolve into tumors under certain conditions. Tumor lesions can evolve asexually and develop an increased ability to invade, grow, metastasize, and heterogeneity, especially when tumor cells escape host immune surveillance. Current cancer therapies may involve surgery, chemotherapy, hormone therapy, and/or radiation therapy to eradicate tumor cells in the patient. The latest evolution of cancer therapeutics is discussed by Rajkumar et al. in Nature Reviews Clinical Oncology 11, 628–630 (2014).

All current cancer therapy methods have significant disadvantages for patients. For example, surgery may be contraindicated due to the patient's health or may be unacceptable. In addition, surgery may not completely remove tumor tissue. When tumor tissue exhibits a higher sensitivity to radiation than normal tissue, only radiation therapy is effective. Radiation therapy can also often cause serious side effects. Hormone therapy is rarely given as a single agent. Although hormone therapy may be effective, it is usually used after other treatments have removed most of the cancer cells to prevent or delay cancer recurrence.

With regard to chemotherapy, there are various chemotherapeutic agents that can be used to treat cancer. Most cancer chemotherapeutic agents act by inhibiting DNA synthesis and by inhibiting the biosynthesis of the deoxyribonucleic acid triphosphate precursor directly or indirectly to prevent DNA replication and accompanying cell division. Gilman et al ., Goodman and Gilman's: The Pharmacological Basis of Therapeutics , edited by Tenth (McGraw Hill, New York).

Although many chemotherapeutic agents are available, chemotherapy has many disadvantages. Stockdale, Medicine , Volume 3, edited by Rubenstein and Federman, Chapter 12, Section 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes serious and often dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression. In addition, even in the case where a combination of chemotherapeutic agents is administered, many tumor cells are resistant to or develop resistance to such chemotherapeutic agents. In fact, those cells that are resistant to the specific chemotherapeutic agents used in the treatment regimen usually prove to be resistant to other drugs, even if their agents work by a mechanism different from the drugs used in the specific treatment. This phenomenon is called multi-drug resistance or multi-drug resistance. Due to drug resistance, many cancers have proved or become standard chemotherapeutic treatments and are difficult to cure.

Diffuse large B-cell lymphoma (DLBCL) accounts for about one-third of non-Hodgkin's lymphoma (NHL). NHL is the fifth most common cancer in men and women in the United States. It is estimated that in 2012 385,700 patients worldwide were diagnosed with NHL and approximately 199,700 patients died due to the disease. (Torre, LA et al . Global cancer statistics, 2012; CA Cancer J. Clin . 65, 87-108 (2015)). DLBCL is the most common form of B-cell NHL. It is estimated that there were 27,650 new cases in the United States in 2016, accounting for approximately 26% of all mature B-cell NHL tumors diagnosed. (Teras, LR et al . 2016 US lymphoid malignancy statistics by World Health Organization subtypes; CA Cancer J. Clin. 66, 443-459 (2016)). Although some patients with DLBCL were cured with traditional chemotherapy, the remaining patients died of the disease.

There is still a significant need for treatment, prevention and management of DLBCL, especially the standard treatment of DLBCL that is difficult to cure such as surgery, radiation therapy, chemotherapy and hormone therapy, while reducing or avoiding the toxicity and/or side effects associated with conventional therapies are safe and effective Methods.

Citation or identification of any reference in this part of the application should not be construed as an admission that the reference is prior art to the application.

或其醫藥學上可接受之鹽、互變異構體、同位素體、或立體異構體，其中R、環A及n為如本文所定義。This article provides compounds having the following formula (I):

Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, wherein R, ring A, and n are as defined herein.

The compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof (each referred to herein as "isoindoline dione compound") is suitable for treatment or prevention DLBCL.

In one aspect, provided herein are isoindoline dione compounds as described in the present invention (such as Table 1).

In one aspect, provided herein is a pharmaceutical composition comprising an effective amount of an isoindolinone compound as described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. In some embodiments, the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal, or topical administration.

In one aspect, provided herein are methods for treating or preventing DLBCL, the methods comprising administering to an individual in need an effective amount of an isoindolinone compound as described herein. In another aspect, provided herein are methods for treating or preventing DLBCL, such methods comprising administering an effective amount of a pharmaceutical composition described herein to an individual in need. In another aspect, provided herein are isoindoline dione compounds as described herein for use in the treatment of DLBCL. In another aspect, provided herein is a pharmaceutical composition as described herein for use in the treatment of DLBCL.

In another aspect, provided herein are methods for preparing isoindoline dione compounds as described herein.

Embodiments of the present invention can be more fully understood by reference to implementations and examples that are intended to illustrate non-limiting embodiments.

This application claims the priority of US Provisional Application No. 62/661,525 filed on April 23, 2018, the entire content of which is incorporated herein by reference. definition

As used herein, the terms "comprising" and "including" are used interchangeably. The terms "comprising" and "including" should be interpreted as indicating the presence of the stated features or the mentioned components, but does not exclude the presence or addition of one or more features, or components, or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples covered by the term "consisting of". Therefore, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

The term "consisting of" means that the subject has at least 90%, 95%, 97%, 98%, or 99% of the stated features or components that make up the subject. In another embodiment, the term "consisting of" excludes any other features or components from any subsequent description, except for those features or components that are not necessary to achieve the technical effect.

As used herein, the term "or" should be interpreted as including "or" to mean any one or any combination. Therefore, "A, B or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C". An exception to this definition will only occur if a combination of elements, functions, steps, or effects are mutually exclusive to some extent.

As used herein and unless otherwise specified, "alkyl" has from 1 to 10 carbon atoms, usually from 1 to 8 carbons, or in some embodiments from 1 to 6, 1 to 4, or Saturated, partially saturated or unsaturated linear or branched acyclic hydrocarbons of 2 to 6 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; and saturated branched alkyl groups include -isopropyl, -second butyl, -Isobutyl, -third butyl, -isopentyl, -neopentyl, -third pentyl, 2-methylpentyl, 3-methylpentyl, -4-methylpentyl,- 2,3-Dimethylbutyl and similar groups. "Alkenyl" is an alkyl group containing one or more carbon-carbon double bonds. "Alkynyl" is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include but are not limited to vinyl, allyl, -CH=CH(CH ₃ ), -CH=C(CH ₃ ) ₂ , -C(CH ₃ )=CH ₂ , -C(CH ₃ )=CH(CH ₃ ), -C(CH ₂ CH ₃ )=CH ₂ , -C≡CH, -C≡C(CH ₃ ), -C≡C(CH ₂ CH ₃ ), -CH ₂ C ≡CH, -CH ₂ C≡C(CH ₃ ), -CH ₂ C≡C(CH ₂ CH ₃ ), and other alkyl groups. The alkyl group can be substituted or unsubstituted. When the alkyl groups described herein are considered "substituted", the alkyl groups may be substituted with any one or more substituents as can be seen in the exemplary compounds and examples disclosed herein The others, and halogen; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkoxy , Aralkyloxy, heterocyclylalkoxy, heteroarylalkoxy, heterocycloalkylalkoxy; pendant (=O); amine, alkylamine, cycloalkylamine , Arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino; imino; amido; amidino; guanidino; enamino; acylamino; sulfamoyl Amino group; urea, nitrourea; oxime; hydroxylamine group; alkoxyamine group; aralkyloxyamine group; hydrazine group; hydrazide group; hydrazide group; azido group; nitro group; thio (- SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acetyl; methylamide; carboxyl; ester; urethane; amide Amino group; cyano group; isocyanate group; isothiocyanate group; cyanate group; thiocyanate group; or -B(OH) ₂ .

As used herein and unless otherwise specified, "cycloalkyl" is a saturated or partially saturated cyclic alkane having from 3 to 10 carbon atoms with a monocyclic ring or multiple condensation or bridging rings optionally substituted base. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Examples of such cycloalkyl groups include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentane Group, 2-methylcyclooctyl, and similar groups, or multiple rings or bridged ring structures, such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1] Heptyl, bicyclic [2.2.2] octyl, adamantyl and similar groups. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and other groups. The cycloalkyl group may be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

As used herein and unless otherwise specified, "aryl" is a group having from 6 to 14 carbon atoms with a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthracenyl) Aromatic carbocyclic groups. In some embodiments, the aryl group contains 6-14 carbons in the ring portion of such groups, and in other embodiments contains from 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl and similar groups. The aryl group may be substituted or unsubstituted. The phrase "aryl groups" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (eg, dihydroindenyl, tetrahydronaphthyl, and the like).

As used herein and unless otherwise specified, "heteroaryl" is an aromatic ring system having one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms of these ring atoms are carbon atom. In some embodiments, in the ring portion of these groups, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments contains from 6 to 9 or even 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include but are not limited to groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (eg, benzene Benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (eg, indole) Indole-2-one), isoindolin-1-one, azaindolyl, pyrrolopyridyl (eg, 1H-pyrrolo[2,3-b]pyridyl), indazolyl, Benzimidazolyl (eg, 1H-benzo[d]imidazolyl), azabenzimidazolyl, imidazopyridyl (eg, 1H-imidazo[4,5-b]pyridyl), pyrazolo Pyridyl, triazolopyridyl, benzotriazolyl (eg, 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (eg, benzo[d]oxazolyl) (Oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guanidinyl, quinolinyl, iso Quinolinyl, 3,4-dihydroisoquinoline-1(2H)-keto, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Heteroaryl groups can be substituted or unsubstituted.

As used herein and unless otherwise specified, "heterocyclyl" is an aromatic ring system (also known as heteroaryl) or a non-aromatic cycloalkyl (also known as heterocycloalkyl) in which the ring carbon One to four of the atoms are independently replaced by heteroatoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. In some embodiments, the heterocyclic group includes 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclic groups can also be bonded to any ring atom of other groups (ie, at any carbon or heteroatom of the heterocycle). The heterocyclic group may be substituted or unsubstituted. Heterocyclic groups encompass unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (eg, imidazolidin-4-one or imidazolidine-2,4-dione). The phrase heterocyclic group includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as 1-aminotetralin and 2-aminotetralin, benzotriazolyl (For example, 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (for example, 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[l , 4] dioxinolyl (dioxinyl), and benzo [l, 3] dioxolyl (dioxolyl). The phrase also includes bridged polycyclic ring systems containing heteroatoms, such as but not limited to quinine ring groups. Representative examples of heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl (eg, imidazolidine- 4-keto or imidazolidine-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, dioxolyl, furanyl, thienyl , Pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (eg, Benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (eg piperazin-2-one) , Morpholinyl, thiomorpholinyl, tetrahydropiperanyl (for example, tetrahydro-2H-piperanyl), tetrahydrothiopyranyl, oxathianyl (oxathianyl), dioxolyl (dioxyl), dithianyl (dithianyl), piperanyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridinyl, dihydrodithiinyl, dihydrodithiinyl, di Dihydrodithionyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, indolyl (eg, indol-2-one), iso Indolin-1-one, indolinyl, isoindolyl, isoindolinyl, azaindolyl, pyrrolopyridyl (eg, 1H-pyrrolo[2,3-b]pyridine Group), indazolyl, indazinyl, benzotriazolyl (eg, 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (eg, 1H-benzo[ d]Imidazolyl or 1H-benzo[d]imidazol-2(3H)-keto), benzofuranyl, benzothienyl, benzothiazolyl, benzoxadiazole, benzoxazinyl, Benzodithiinyl (benzodithiinyl), benzoxathiinyl (benzoxathiinyl), benzothithiyl, benzoxazolyl (eg, benzo[d]oxazolyl), benzothiazolyl, benzene Thiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl (for example, 1H-pyrazolyl[3,4-b]pyridyl, 1H-pyrazolo[ 4,3-b]-pyridyl), azabenzimidazolyl, imidazopyridyl (eg, 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolo Pyridyl, purine, xanthine, adenine, guanidino, quinolinyl, isoquinolinyl, 3,4-dihydroisoquinoline-1(2H)-keto, quinazinyl, quinoxa Porphyrinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thienyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, di Dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydro Pyrazolopyridyl, tetrahydroimidazopyridyl , Tetrahydrotriazolopyridinyl, tetrahydropyrimidin-2(1H)-one and tetrahydroquinolinyl. Representative non-aromatic heterocyclic groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclic groups include aziridinyl, azetidine, azacycloheptyl, pyrrolidinyl, imidazolidinyl (eg, imidazolidin-4-one or imidazolidine-2 ,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (eg piperazin-2-one), morpholinyl, thio Morpholinyl, tetrahydropiperanyl (e.g., tetrahydro-2H-piperanyl), tetrahydrothiopyranyl, oxysulfanyl, dithioalkyl, 1,4-dioxaspiro[4.5]dec Group, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclic groups may be mono-substituted or substituted more than once, such as but not limited to pyridyl or morpholinyl, which are 2-, 3-, 4-, 5-, or 6-substituted, or Two substitutions by different substituents such as those listed below.

As used herein, the following heterocyclic group names refer to the structures in the table below. In some embodiments, the point of attachment is via a ring nitrogen atom.

As used herein and unless otherwise indicated, "cycloalkylalkyl" is a group of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups can be substituted at the alkyl, cycloalkyl or both alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, Cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl and similar groups.

As used herein and unless otherwise specified, "aralkyl" is a group of the formula: -alkyl-aryl, where alkyl and aryl are as defined above. The substituted aralkyl group may be substituted at the alkyl, aryl, or both alkyl and aryl parts of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and aralkyl groups having an aryl group fused to a cycloalkyl group, such as indan-4-ylethyl.

As used herein and unless otherwise specified, "heterocyclylalkyl" is a group of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined above. "Heteroarylalkyl" is a group of the following formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are as defined above. "Heterocycloalkylalkyl" is a group of the following formula: -Alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl are as defined above. Substituted heterocycloalkyl groups can be substituted at the alkyl, heterocyclyl, or both alkyl and heterocyclyl portions of the group. Representative heterocycloalkyl groups include but are not limited to morpholin-4-ylethyl, morpholin-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl Group, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

As used herein and unless otherwise indicated, "halogen" is fluorine, chlorine, bromine, or iodine.

As used herein and unless otherwise specified, "hydroxyalkyl" is an alkyl group substituted with one or more hydroxyl groups as described above.

As used herein and unless otherwise specified, "alkoxy" is -O-(alkyl), where alkyl is as defined above. "Alkylthio" is -S-(alkyl), where alkyl is as defined above.

As used herein and unless otherwise indicated, "alkoxyalkyl" is -(alkyl)-O-(alkyl), where alkyl is as defined above.

As used herein and unless otherwise indicated, "cycloalkyloxy" is -O-(cycloalkyl), where cycloalkyl is as defined above.

As used herein and unless otherwise specified, "aryloxy" is -O-(aryl), where aryl is as defined above.

As used herein and unless otherwise specified, "heterocyclyloxy" is -O-(heteroalkyl), wherein heteroalkyl is as defined above. "Heteroaryloxy" is -O-(heteroaryl), wherein heteroaryl is as defined above. "Heterocycloalkyloxy" is -O-(heterocycloalkyl), wherein heterocycloalkyl is as defined above.

As used herein and unless otherwise specified, "amino" is a group of the formula: -NH ₂ , -NH(R ^# ), or -N(R ^# ) ₂ , where each R ^{# is} independently Alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic (e.g., heteroaryl or heterocycloalkyl), or heterocycloalkyl (e.g. hetero (Arylalkyl or heterocycloalkylalkyl), each of which is independently substituted or unsubstituted.

In one embodiment, "amino" is "alkylamino", which is a group of the following formula: -NH-alkyl or -N(alkyl) ₂ , wherein each alkyl group Independently defined as above. The terms ``cycloalkylamino'', ``arylamino'', ``heterocyclylamino'', ``heteroarylamino'', ``heterocycloalkylamine''"Heterocycloalkylamino" or similar terms reflect the above description of "alkylamino", where the term "alkyl" is respectively "cycloalkyl", "aryl", "heterocyclic", "heteroaryl"","heterocycloalkyl" or similar terms.

As used herein and unless otherwise specified, "carboxy" is a group of the formula: -C(O)OH.

As used herein and unless otherwise specified, "acyl" is a group of the formula: -C(O)(R ^# ) or -C(O)H, where R ^# is as defined above. "Formyl" is a group of the following formula: -C(O)H.

As used herein and unless otherwise specified, "amido" is a group of the formula: -C(O)-NH ₂ , -C(O)-NH(R ^# ), -C(O) -N(R ^# ) ₂ , -NH-C(O)H, -NH-C(O)-(R ^# ), -N(R ^# )-C(O)H, or -N(R ^# ) -C(O)-(R ^# ), where each R ^{# is} independently defined above.

In one embodiment, "acylamino" is "aminocarbonyl", which is a group of the following formula: -C(O)-NH ₂ , -C(O)-NH(R ^# ), -C(O)-N(R ^# ) ₂ , where each R ^{# is} independently defined above.

In one embodiment, "acylamino" is "acylamino", which is a group of the following formula: -NH-C(O)H, -NH-C(O)-(R ^# ), -N(R ^# )-C(O)H, or -N(R ^# )-C(O)-(R ^# ), where each R ^{# is} independently defined above.

As used herein and unless otherwise specified, "sulfonylamino" is a group of the formula: -NHSO ₂ (R ^# ) or -N(R ^# )SO ₂ (R ^# ), where each R ^# defined as above.

As used herein and unless otherwise specified, the "ester" group is a group of the formula: -C(O)-O-(R ^# ) or -OC(O)-(R ^# ), where R ^# As defined above.

In one embodiment, the "ester" group is "alkoxycarbonyl", which is a group of the following formula: -C(O)-O-(alkyl), wherein alkyl is as defined above . The terms ``cycloalkyloxycarbonyl'', ``aryloxycarbonyl (aryloxycarbonyl)'', ``heterocyclyloxycarbonyl (heterocyclyloxycarbonyl)'', ``heteroaryloxycarbonyl (heteroaryloxycarbonyl)'', ``heterocyclic alkoxycarbonyl'' "Heterocycloalkyloxycarbonyl" or similar terms reflect the above description of "alkoxycarbonyl", where the term "alkoxy" is respectively "cycloalkoxy", "aryloxy", "heterocyclicoxy", Substitution of "heteroaryloxy", "heterocyclic alkoxy" or similar terms.

As used herein and unless otherwise specified, the "carbamate" group is a group of the formula: -OC(O)-NH ₂ , -OC(O)-NH(R ^# ), -OC( O)-N(R ^# ) ₂ , -NH-C(O)-O-(R ^# ), or -N(R ^# )-C(O)-O-(R ^# ), where each R ^{# is} independent The ground is as defined above.

As used herein and unless otherwise specified, the "urea" group is a group of the formula: -NH(CO)NH ₂ , -NHC(O)NH(R ^# ), -NHC(O)N(R ^# ) ₂ , -N(R ^# )C(O)NH ₂ , -N(R ^# )C(O)NH(R ^# ), or -N(R ^# )C(O)N(R ^# ) ₂ , Where each R ^{# is} independently defined above.

As used herein and unless otherwise specified, "sulfinyl" is a group of the formula: -S(O)R ^# , where R ^# is as defined above.

As used herein and unless otherwise specified, "sulfonyl" is a group of the formula: -S(O) ₂ R ^# , where R ^# is as defined above.

As used herein and unless otherwise specified, "aminosulfonyl" is a group of the formula: -SO ₂ NH ₂ , -SO ₂ NH(R ^# ), or -SO ₂ N(R ^# ) ₂ , where each R ^{# is} independently defined above.

When groups (other than alkyl groups) described herein are considered "substituted", these groups may be substituted with any suitable substituent(s). Illustrative examples of substituents are the exemplary compounds disclosed herein and those visible in the examples, as well as halogen; optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetero Cyclic, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heterocycloalkyl, heteroarylalkyl, heterocycloalkylalkyl; hydroxyl; alkoxy; cycloalkyloxy Group, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkoxy, aralkyloxy, heterocyclylalkoxy, heteroarylalkyl Oxygen, heterocycloalkylalkoxy; pendant (=O); oxide (for example, nitrogen atom substituted with oxide is called N-oxide); amine group, alkylamine group, cycloalkyl group Amino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino; imino; imino; acylamido; guanidino; enamino; acylamino Sulfonylamido; urea, nitrourea; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; hydrazine; hydrazide; hydrazide; azido; nitro; sulfur Substitution (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acetyl; methylamide; carboxyl; ester; carbamic acid Ester; amide group; cyano group; isocyanate group; isothiocyanate group; cyanate group; thiocyanate group; or -B(OH) ₂ .

As used herein, the term "Isoindolinedione Compound" refers to the compound of formula (I) and other examples provided herein. In one embodiment, the "isoindoline dione compounds" are the compounds listed in Table 1. The term "isoindoline dione compound" includes pharmaceutically acceptable salts, tautomers, isotopes, and stereoisomers of the compounds provided herein.

As used herein, the term "pharmaceutically acceptable salt(s)" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, which includes inorganic acids and bases and organic Acid and alkali. Suitable pharmaceutically acceptable base addition salts of the compound of formula (I) include, but are not limited to, metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc or of amine acid, N, N' -Organic salts made of dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucosamine) and procaine. Suitable non-toxic acids include but are not limited to inorganic and organic acids, such as acetic acid, alginic acid, o-aminobenzoic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, formic acid, fumaric acid, furoic acid , Galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid , Nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Examples of specific salts therefore include hydrochloride and mesylate. Other examples known in the art, see, e.g. Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990 ) or Remington: The Science and Practice of Pharmacy , 19th ed., Mack Publishing, Easton PA (1995 ).

As used herein and unless otherwise specified, the term "stereoisomer" or "stereomerically pure" means an isoindoline dione compound that is substantially free of other compounds A stereoisomer of stereoisomers. For example, a stereomerically pure compound with a palm center is substantially free of the relative mirror image isomer of the compound. A stereomerically pure compound with two opposite palm centers will be substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, and greater than about 90% by weight of a stereoisomer of the compound Structure and less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than About 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. The isoindoline dione compounds may have paracentric centers and exist as racemates, individual mirror isomers or diastereomers, and mixtures thereof. All such isomeric forms are included in the embodiments disclosed herein, including mixtures thereof.

The use of stereoisomerically pure forms of these isoindoline dione compounds and the use of mixtures of these forms are covered by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of mirror isomers of specific isoindoline dione compounds can be used in the methods and compositions disclosed herein. Such isomers can be synthesized or resolved asymmetrically using standard techniques such as palm column or palm resolving agents. See, for example, Jacques, J. et al ., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH et al ., Tetrahedron 33: 2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions page 268 (Edited by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

It should be noted that the isoindoline dione compounds may include E and Z isomers or mixtures thereof, and cis and trans isomers or mixtures thereof. In certain embodiments, the isoindoline dione compounds are separated into E or Z isomers. In other embodiments, the isoindoline dione compound is a mixture of E and Z isomers.

。"Tautomer" refers to the isomeric forms of the compound in equilibrium with each other. The concentration of the isomeric form will depend on the environment in which the compound is found and may vary depending on, for example, whether the compound is solid or in the form of an organic solution or aqueous solution. For example, in an aqueous solution, pyrazole can exhibit the following isomer forms, which are called tautomers of each other:

.

As is well understood by those skilled in the art, various functional groups and other structures can exhibit tautomerism and all tautomers of the compound of formula (I) are within the scope of the present invention.

It should also be noted that isoindoline dione compounds may contain unnatural proportions of atomic isotopes at one or more atoms. For example, these compounds may be radioactively labeled with radioisotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), sulfur-35 ( ³⁵ S) or carbon-14 ( ¹⁴ C), or may be used such as deuterium ( ² H ), carbon-13 ( ¹³ C), or nitrogen-15 ( ¹⁵ N) isotope enrichment. As used herein, "isotopic bodies" are compounds that are enriched in isotopes. The term "isotopically enriched" means that the atom has an isotopic composition that is different from the natural isotopic composition of the atom. "Isotopically enriched" may also mean that the compound contains at least one atom with an isotopic composition different from the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents, such as cancer therapeutic agents, research reagents (eg, binding analysis reagents), and diagnostic reagents (eg, in vivo imaging reagents). All isotopic variants of isoindoline dione compounds as described herein, whether radioactive or not, are intended to be covered by the examples provided herein. In some embodiments, isotope bodies of isoindoline dione compounds are provided, for example, the isotope bodies are deuterium, carbon-13, and/or nitrogen-15 enriched isoindoline dione compounds. As used herein, means a compound "deuterated", wherein at least one hydrogen (H) has been deuterium (indicated by D or ² H) substitution, i.e. the compound deuterium enriched in at least one position.

It should be understood that independent of the stereoisomeric or isotopic composition, the various isoindoline dione compounds mentioned herein may be provided in the form of any pharmaceutically acceptable salts discussed herein. Likewise, it should be understood that the isotopic composition can be changed independently of the stereoisomeric composition of the various isoindoline dione compounds mentioned herein. In addition, although the isotopic composition is not limited to those corresponding to isoindoline dione compounds or their salts, it can be changed independently of the selection of the pharmaceutically acceptable salts corresponding to isoindoline dione compounds .

It should be noted that if there is a conflict between the structure depicted and the name of the structure, the structure depicted shall prevail.

As used herein, "treating" means reducing, in whole or in part, one or more symptoms of a disorder, disease or condition, or related to the disorder, disease or condition, or slowing or preventing the further evolution of their symptoms or Worsen, or reduce or eradicate the cause of the disorder, disease, or condition itself. In one embodiment, the disorder is DLBCL or symptoms thereof as described herein.

As used herein, "Preventing" means delaying and/or excluding, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition; preventing an individual from acquiring a disorder, disease, or condition; or reducing an individual from acquiring a disorder, Method of risk of disease or condition. In one embodiment, the disorder is DLBCL or symptoms thereof as described herein.

The term "effective amount" in combination with an isoindoline dione compound means an amount capable of treating or preventing the conditions, diseases or conditions disclosed herein, or symptoms thereof.

The term "individual" includes animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs, in one embodiment It is a mammal, in another embodiment a human. In one embodiment, the individual is a human suffering from or at risk of having DLBCL or its symptoms.

Generally, the technical teachings of one embodiment can be combined with the teachings described in other embodiments provided herein. Isoindoline dione

或其醫藥學上可接受之鹽、互變異構體、同位素體、或立體異構體， 其中： 環A為視情況經取代之非芳族雜環基(其中連接點處於環氮原子上)； 各R為獨立地經取代或未經取代之C_1-3 烷基、或鹵素；且 n為0、1、2、3或4。This article provides compounds having the following formula (I):

Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, wherein: Ring A is an optionally substituted non-aromatic heterocyclic group (where the connection point is on the ring nitrogen atom) ; Each R is independently substituted or unsubstituted C _1-3 alkyl, or halogen; and n is 0, 1, 2, 3, or 4.

， 或其醫藥學上可接受之鹽、互變異構體、同位素體、或立體異構體，其中環A及R為如本文所定義。In some embodiments, the compound is a compound of formula (II)

, Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, wherein rings A and R are as defined herein.

， 或其醫藥學上可接受之鹽、互變異構體、同位素體、或立體異構體，其中環A及R為如本文所定義。In some embodiments, the compound is a compound of formula (III)

, Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, wherein rings A and R are as defined herein.

， 或其醫藥學上可接受之鹽、互變異構體、或同位素體，其中環A、n及R為如本文所定義。In some embodiments, the compound is a compound of formula (IV)

, Or a pharmaceutically acceptable salt, tautomer, or isotope thereof, wherein rings A, n, and R are as defined herein.

， 或其醫藥學上可接受之鹽、互變異構體、或同位素體，其中環A及R為如本文所定義。In some embodiments, the compound is a compound of formula (V)

, Or a pharmaceutically acceptable salt, tautomer, or isotope thereof, wherein Rings A and R are as defined herein.

， 或其醫藥學上可接受之鹽、互變異構體、或同位素體，其中環A及R為如本文所定義。In some embodiments, the compound is a compound of formula (VI)

, Or a pharmaceutically acceptable salt, tautomer, or isotope thereof, wherein Rings A and R are as defined herein.

， 或其醫藥學上可接受之鹽、互變異構體、或同位素體，其中環A、n及R為如本文所定義。In some embodiments, the compound is a compound of formula (VII)

, Or a pharmaceutically acceptable salt, tautomer, or isotope thereof, wherein rings A, n, and R are as defined herein.

， 或其醫藥學上可接受之鹽、互變異構體、或同位素體，其中環A及R為如本文所定義。In some embodiments, the compound is a compound of formula (VIII)

, Or a pharmaceutically acceptable salt, tautomer, or isotope thereof, wherein Rings A and R are as defined herein.

， 或其醫藥學上可接受之鹽、互變異構體、或同位素體，其中環A及R為如本文所定義。In some embodiments, the compound is a compound of formula (IX)

, Or a pharmaceutically acceptable salt, tautomer, or isotope thereof, wherein Rings A and R are as defined herein.

In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is selected from The following optionally substituted non-aromatic heterocyclic groups: azetidine; piperidinyl; piperazinyl; morpholinyl; 5-azaspiro[2,3]hexyl; 2-azaspiro [3.3]heptyl; 2-oxa-6-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl; 6 -Oxa-2-azaspiro[3.4]octyl; 2-azaspiro[3.5]nonyl; 7-oxa-2-azaspiro[3.5]nonyl; octahydrocyclopenta[c] Pyrrolyl; 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl; 6-azaspiro[3.4]octyl; 2-oxa-6-azaspiro[3.4] Octyl; 6-azaspiro[2.5]octyl; 7-azaspiro[3.5]nonyl; 1-oxa-8-azaspiro[4.5]decyl; 2-oxa-8-aza Spiro[4.5]decyl; 2,8-diazaspiro[4.5]dec-1-one; 3-oxa-9-azaspiro[5.5]undecyl; 1,4-oxazo Group; 8-azabicyclo[3.2.1]octyl; and isoindolinyl. In one embodiment, Ring A is an optionally substituted non-aromatic heterocyclic group selected from the group consisting of: azetidinyl; piperidinyl; piperazinyl; 5-azaspiro[2,3] Hexyl; 2-azaspiro[3.3]heptyl; 2-oxa-6-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro [3.4] Octyl; 6-oxa-2-azaspiro[3.4]octyl; 2-azaspiro[3.5]nonyl; 7-oxa-2-azaspiro[3.5]nonyl; octa Hydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl; 6-azaspiro[3.4]octyl; 2-oxa-6 -Azaspiro[3.4]octyl; 6-azaspiro[2.5]octyl; 7-azaspiro[3.5]nonyl; 1-oxa-8-azaspiro[4.5]decyl; 2- Oxa-8-azaspiro[4.5]decyl; 2,8-diazaspiro[4.5]dec-1-oneyl; 3-oxa-9-azaspiro[5.5]undecyl; 1,4-oxazo; 8-azabicyclo[3.2.1]octyl; and isoindolinyl. In another embodiment, Ring A is an optionally substituted non-aromatic heterocyclic group selected from the group consisting of: azetidine; piperidinyl; piperazinyl; 2-azaspiro[3.3]heptane Group; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl; 7-oxa-2-azaspiro[3.5]nonyl; 1-oxa- 8-azaspiro[4.5]decyl; and 2,8-diazaspiro[4.5]dec-1-one. In another embodiment, Ring A is an optionally substituted non-aromatic heterocyclic group selected from the group consisting of: azetidinyl; piperidinyl; piperazinyl; and morpholinyl. In another embodiment, Ring A is optionally substituted azetidine. In another embodiment, Ring A is optionally substituted piperidinyl. In another embodiment, Ring A is optionally substituted piperazinyl. In another embodiment, Ring A is optionally substituted morpholinyl.

In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is substituted by one or Multiple substituents independently selected from the group consisting of halogen, C _1-6 alkyl, OR ¹ , CON(R ² ) ₂ , SO ₂ (C _1-4 alkyl), N(R ² )SO ₂ ( C _1-4 alkyl), -(C _0-3 alkyl)-(C _3-7 cycloalkyl), (non-aromatic heterocyclic group), aryl, heteroaryl, O-aryl, O -Heteroaryl, and C(O)aryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; where R ¹ is H, optionally substituted C _1-6 alkyl, or optionally substituted -(C _0-3 alkyl)-(C _3-7 cycloalkyl); and each R ^{2 is} independently H, or C _1-6 alkyl . In other embodiments, Ring A is substituted with one or more substituents independently selected from the group consisting of: F, Cl, Br, CH ₃ , CH ₂ CH ₃ , n-propyl, isopropyl, n-butyl, Dibutyl, isobutyl, tertiary butyl, n-pentyl, isopentyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ CF ₃ , CH(CH ₃ ) CF ₃ , CH ₂ CH ₂ CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , O-isopropyl, O-n-propyl, O-n-butyl, O-isobutyl, O-third Butyl, OCF ₃ , O-cyclopropyl, O-cyclobutyl, OCH ₂ -cyclopropyl, OCH ₂ -cyclobutyl, CONH ₂ , CONH(CH ₃ ), CON(CH ₃ ) ₂ , SO ₂ CH ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, CH ₂ -cyclopropyl, CH ₂ -cyclobutyl; (non-aromatic heterocyclic group), its choice From azetidinyl, pyrrolidinyl, pyrrolidinyl, isothiazolidinyl, isothiazolidine 1,1-dioxyyl (isothiazolidine 1,1-dioxidyl), piperidinyl, piperazinyl, Porphyrinyl, 3-oxa-8-azabicyclo[3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, where the heterocyclyl is optionally substituted by one or A plurality of substituents independently selected from CH ₃ , CH ₂ CH ₃ , or CF _{3 are} substituted; phenyl, O-phenyl, or C(O)-phenyl, wherein the phenyl is optionally substituted by one or more Selected from F, Cl, CH ₃ , CN, or CONH ₂ substituents; heteroaryl, selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazole Oxazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, or benzisoxazolyl, wherein the heteroaryl group is optionally selected from one or more independently selected from F, Cl, CF ₃ , CN, CONH ₂ , CONH(CH ₃ ) ₂ or CON(CH ₃ ) ₂ substituent substitution; O-pyridyl and O-pyrimidinyl. In some embodiments, Ring A is substituted with one or more substituents independently selected from the group consisting of: F, CH ₃ , CH ₂ CH ₃ , isopropyl, third butyl, CH ₂ F, CF ₃ , CH (CH ₃ )CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , O-isopropyl, O-n-propyl, O-isobutyl, O-third butyl, OCF ₃ , O-cyclobutyl , OCH ₂ -cyclopropyl, CON(CH ₃ ) ₂ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, CH ₂ -cyclopropyl; (non-aromatic heterocyclic Group) selected from pyrrolidinyl, pyrrolidinyl, isothiazolidine 1,1-dioxy, morpholinyl, 3-oxa-8-azabicyclo[3.2.1]octyl, or 8 -Oxa-3-azabicyclo[3.2.1]octyl, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from CH ₃ ; phenyl, O-phenyl or C( O)-phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH ₃ , CN, or CONH ₂ ; heteroaryl, which is selected from pyrazolyl, oxo Oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, or benzisoxazolyl, where the heteroaryl group is optionally selected from one or more independently selected from F, Cl , CF ₃ , CN, CONH ₂ , CON(CH ₃ ) ₂ substituent substitution; O-pyridyl and O-pyrimidinyl.

In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is Or more azetidinyl groups substituted independently by the following substituents: C _1-6 alkyl, (non-aromatic heterocyclic group), aryl, heteroaryl, O-aryl, and O- Heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. In some such embodiments, ring A is azetidinyl substituted with one or more substituents independently selected from CH ₂ CH ₃ , n-propyl, isopropyl, n-butyl, Second butyl, isobutyl, third butyl; CF ₃ ; pyrrolidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl, which is optionally substituted with one or more CH ₃ ; 3-oxa-8-azabicyclo[3.2.1]octyl; 8-oxa-3-azabicyclo[3.2.1]octyl; pyrazolyl; 2-pyridyl; 3-pyridyl; 4-pyridyl, phenyl; and O-phenyl; wherein the phenyl is optionally substituted with one or more substituents selected from F or CN. In other embodiments, ring A is azetidinyl substituted with one or more substituents independently selected from: CH ₂ CH ₃ , isopropyl, third butyl; CF ₃ ; pyrrolidine Pyrrolidinone; morpholinyl, which is optionally substituted with one or more CH ₃ ; 3-oxa-8-azabicyclo[3.2.1]octyl; 8-oxa-3-aza Bicyclo[3.2.1]octyl; pyrazolyl; 2-pyridyl; 3-pyridyl; phenyl; and O-phenyl; where the phenyl is optionally substituted by one or more selected from F or CN Radical substitution. In one embodiment, ring A is an azetidinyl group optionally substituted with morpholinyl. In some such embodiments, R is F and n is 1. In some such embodiments, the compound is a compound of formula (II) and R is F. In other such embodiments, the compound is a compound of formula (III) and R is F. In other such embodiments, the compound is of formula (IV), R is F and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F. In other such embodiments, the compound is a compound of formula (VI) and R is F. In other such embodiments, the compound is a compound of formula (VII), R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In other such embodiments, the compound is a compound of formula (IX) and R is F. In some such embodiments, the compound is a compound of formula (II) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (III) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (IV), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (VI) and R is CH ₃ . In other such embodiments, the compound is of formula (VII), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (IX) and R is CH ₃ .

其中R^a 為H且R^b 為C_1-6 烷基、非芳族雜環基、芳基、雜芳基、或O-芳基；或R^a 及R^b 連同其所連接之碳一起形成3-6員環烷基或4-6員非芳族雜環基；其中該烷基、環烷基、雜環基、芳基、或雜芳基視情況被一或多個鹵素、C_1-3 烷基、或CN取代。In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is

Wherein R ^a is H and R ^b is a C _1-6 alkyl group, non-aromatic heterocyclic group, aryl, heteroaryl, O-, or aryl; or R ^a and R ^b form together with the carbon they are attached 3-6 member cycloalkyl or 4-6 member non-aromatic heterocyclic group; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally substituted by one or more halogen, C _{1 -3} alkyl, or CN substitution.

In some such embodiments, R ^a is H, and R ^b is CH ₂ CH _3, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; CF ₃ ; Pyrrolidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl, which is optionally substituted with one or more CH ₃ ; 3-oxa-8-azabicyclo[3.2.1]oct Group; 8-oxa-3-azabicyclo[3.2.1]octyl; pyrazolyl; 2-pyridyl; 3-pyridyl; phenyl; or O-phenyl; where the phenyl is optionally One or more substituents selected from F or CN are substituted. In some such embodiments, R ^a is H and R ^b is CH ₂ CH ₃ , isopropyl, third butyl, CF ₃ , pyrrolidinyl; pyrrolidinyl; piperidinyl; piperazinyl ; Morpholinyl, which is optionally substituted with one or more CH ₃ ; 3-oxa-8-azabicyclo[3.2.1]octyl; 8-oxa-3-azabicyclo[3.2.1] Octyl; pyrazolyl; 2-pyridyl; 3-pyridyl; phenyl; or O-phenyl; wherein the phenyl is optionally substituted with one or more substituents selected from F or CN. In some such embodiments, R ^a is H and R ^b is CH ₂ CH ₃ , isopropyl, third butyl, CF ₃ , pyrrolidinyl; pyrrolidinyl, morpholinyl, 2,2 -Dimethylmorpholinyl, 3,3-dimethylmorpholinyl, 2,6-dimethylmorpholinyl, 3,5-dimethylmorpholinyl, 3-oxa-8-aza Bicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, pyrazolyl, 2-pyridyl, 3-pyridyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, O-phenyl, or O-4-cyanophenyl. In one embodiment, R ^a and R ^b together with the carbon to which they are attached form cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, cyclohexyl, oxetanyl , Tetrahydrofuranyl, or Tetrahydropiperanyl. In some such embodiments, the compound is a compound of formula (II) and R is F. In other such embodiments, the compound is a compound of formula (III) and R is F. In other such embodiments, the compound is of formula (IV), R is F and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F. In other such embodiments, the compound is a compound of formula (VI) and R is F. In other such embodiments, the compound is a compound of formula (VII), R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In other such embodiments, the compound is a compound of formula (IX) and R is F. In some such embodiments, the compound is a compound of formula (II) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (III) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (IV), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (VI) and R is CH ₃ . In other such embodiments, the compound is of formula (VII), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (IX) and R is CH ₃ .

In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is Or a plurality of piperidinyl groups substituted independently by the following substituents: halogen, C _1-6 alkyl, OR ¹ , CON(R ² ) ₂ , SO ₂ (C _1-4 alkyl), C _{3- 7} Cycloalkyl, non-aromatic heterocyclic group, aryl, heteroaryl, and O-heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is as appropriate Substituted; wherein R ¹ is H, optionally substituted C _1-6 alkyl, or optionally substituted -(C _0-3 alkyl)-(C _3-7 cycloalkyl); and each R ^{2 is} independently H, or C _1-6 alkyl. In other embodiments, ring A is piperidinyl substituted with one or more substituents independently selected from the group consisting of: F, Cl, CH ₃ , CH ₂ CH ₃ , n-propyl, isopropyl, n-butyl , Second butyl, isobutyl, third butyl, CH ₂ F, CHF ₂ , CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , O-n-propyl, O-isopropyl, O-n Butyl, O-isobutyl, O-third butyl, OCF ₃ , O-cyclopropyl, O-cyclobutyl, OCH ₂ -cyclopropyl, OCH ₂ -cyclobutyl, CONH ₂ , CONH ( CH ₃ ), CON(CH ₃ ) ₂ , SO ₂ CH ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, pyrrolidone, isothiazolidine 1,1- Dioxy, morpholinyl; tetrahydrofuranyl, tetrahydropiperanyl, pyrazolyl; oxadiazolyl, which is optionally substituted with CH ₃ ; phenyl, which is optionally substituted with one or more F; 2- Pyridyl, 3-pyridyl, 4-pyridyl, O-2-pyridyl, O-3-pyridyl, and O-4-pyridyl. In some embodiments, ring A is piperidinyl substituted with one or more substituents independently selected from the group consisting of: F, CH ₃ , CH ₂ CH ₃ , isopropyl, third butyl, CHF ₂ , CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , O-isopropyl, O-isobutyl, O-third butyl, OCF ₃ , O-cyclobutyl, OCH ₂ -cyclopropyl, CON(CH ₃ ) ₂ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, pyrrolidone, isothiazolidine 1,1-dioxy, morpholinyl; tetrahydropiperanyl, pyrazole Group, oxadiazolyl, which is substituted by CH ₃ ; phenyl, which is substituted by one or more F; 2-pyridyl, and O-2-pyridyl. In some such embodiments, the compound is a compound of formula (II) and R is F. In other such embodiments, the compound is a compound of formula (III) and R is F. In other such embodiments, the compound is of formula (IV), R is F and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F. In other such embodiments, the compound is a compound of formula (VI) and R is F. In other such embodiments, the compound is a compound of formula (VII), R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In other such embodiments, the compound is a compound of formula (IX) and R is F. In some such embodiments, the compound is a compound of formula (II) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (III) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (IV), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (VI) and R is CH ₃ . In other such embodiments, the compound is of formula (VII), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (IX) and R is CH ₃ .

其中R^c 為H、鹵素、OH、或(C_1-3 烷基)；且R^d 為視情況經取代之(C_1-3 烷基)、OR¹ 、C(O)N(R² )₂ 、SO₂ (C_1-4 烷基)、C_3-7 環烷基、非芳族雜環基、芳基、雜芳基、或O-雜芳基；或R^c 及R^d 連同其所連接之碳一起形成3-6員環烷基或4-6員非芳族雜環基；其中R¹ 為H、視情況經取代之C_1-6 烷基、或視情況經取代之-(C_0-3 烷基)-(C_3-7 環烷基)；各R² 獨立地為H或C_1-6 烷基；且其中該烷基、環烷基、雜環基、芳基、或雜芳基視情況被一或多個鹵素、C_1-3 烷基、或CN取代。In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is

Where R ^c is H, halogen, OH, or (C _1-3 alkyl); and R ^d is optionally substituted (C _1-3 alkyl), OR ¹ , C(O)N(R ² ) ₂ , SO ₂ (C _1-4 alkyl), C _3-7 cycloalkyl, non-aromatic heterocyclic group, aryl group, heteroaryl group, or O-heteroaryl group; or R ^c and R ^d together with its The attached carbons together form a 3-6 member cycloalkyl or 4-6 member non-aromatic heterocyclic group; wherein R ¹ is H, optionally substituted C _1-6 alkyl, or optionally substituted- (C _0-3 alkyl)-(C _3-7 cycloalkyl); each R ^{2 is} independently H or C _1-6 alkyl; and wherein the alkyl, cycloalkyl, heterocyclyl, aryl , Or heteroaryl is optionally substituted with one or more halogen, C _1-3 alkyl, or CN.

In some such embodiments, R ^c is H, OH, F, CH ₃ , or CH ₂ CH ₃ . In other embodiments, ^Rd is CH ₃ , CH ₂ CH ₃ , n-propyl, isopropyl, n-butyl, second butyl, isobutyl, third butyl, CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ CH ₃ , O-n-propyl, O-isopropyl, O-n-butyl, O-isobutyl, O-third butyl, OCF ₃ , O-cyclopropyl , O-cyclobutyl, OCH ₂ -cyclopropyl, OCH ₂ -cyclobutyl, CONH ₂ , CONH(CH ₃ ), CON(CH ₃ ) ₂ , SO ₂ CH ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -Isopropyl, cyclopropyl, cyclobutyl, pyrrolidone, isothiazolidine 1,1-dioxy, morpholinyl, tetrahydrofuranyl, tetrahydropiperanyl, pyrazolyl; oxadiazole Group, which is optionally substituted by CH ₃ ; phenyl, which is optionally substituted by one or more F; 2-pyridyl, 3-pyridyl, 4-pyridyl, O-2-pyridyl, O-3- Pyridyl, or O-4-pyridyl. In other embodiments, ^Rd is CH ₃ , CH ₂ CH ₃ , isopropyl, third butyl, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ CH ₃ , O-isopropyl, O-isobutyl Group, O-tert-butyl, OCF ₃ , O-cyclobutyl, OCH ₂ -cyclopropyl, CON(CH ₃ ) ₂ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, Pyrrolidone, isothiazolidine 1,1-dioxy, morpholinyl, tetrahydropiperanyl, pyrazolyl, 2-methyl-1,3,4-oxadiazolyl, 3,5- Difluorophenyl, 2-pyridyl, or O-2-pyridyl. In one embodiment, R ^a and R ^b together with the carbon to which they are attached form cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, pyrrolidone, 1-methylpyrrolidone , Tetrahydrofuranyl, 2,2-dimethyltetrahydrofuranyl, or tetrahydropiperanyl. In some such embodiments, the compound is a compound of formula (II) and R is F. In other such embodiments, the compound is a compound of formula (III) and R is F. In other such embodiments, the compound is of formula (IV), R is F and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F. In other such embodiments, the compound is a compound of formula (VI) and R is F. In other such embodiments, the compound is a compound of formula (VII), R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In other such embodiments, the compound is a compound of formula (IX) and R is F. In some such embodiments, the compound is a compound of formula (II) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (III) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (IV), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (VI) and R is CH ₃ . In other such embodiments, the compound is of formula (VII), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (IX) and R is CH ₃ .

In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is Or one or more piperazinyl groups independently substituted by the following substituents: C _1-6 alkyl, SO ₂ (C _1-4 alkyl), -(C _0-3 alkyl)-(C _3-7 ring Alkyl), aryl, heteroaryl, and CO-aryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted. In other embodiments, Ring A is piperazinyl substituted with one or more substituents independently selected from CH ₃ , CH ₂ CH ₃ , n-propyl, isopropyl, n-butyl, and second butyl Group, isobutyl, tertiary butyl, CF ₃ , CH ₂ CF ₃ , CH(CH ₃ )CF ₃ , SO ₂ CH ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, Cyclobutyl, (CH ₂ )cyclopropyl, (CH ₂ )cyclobutyl, phenyl, which are optionally substituted by one or more Cl, F, CN, CH ₃ , CONH ₂ ; pyrazolyl, which In some cases, it is substituted by CH ₃ or CH ₂ CH ₃ ; oxazolyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; oxadiazolyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; thiadiazolyl , Which is optionally substituted with CH ₃ , CH ₂ CH ₃ , or CF ₃ ; 2-pyridyl, 3-pyridyl, or 4-pyridyl, each of which is optionally Cl, F, CF ₃ , CN, CONH ₂ , CONH(CH ₃ ) or CON(CH ₃ ) ₂ ; pyrazinyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; pyrimidinyl, which is optionally substituted by OCH ₃ ; benzisoxazolyl; And CO (phenyl), where the phenyl is optionally fluorinated. In other embodiments, ring A is piperazinyl substituted with one or more substituents independently selected from: CH ₃ , isopropyl, third butyl, CH(CH ₃ )CF ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, (CH ₂ )cyclopropyl, phenyl, which are optionally substituted by one or more Cl, F, CN, CH ₃ , CONH ₂ ; Pyrazolyl, which is optionally substituted by CH ₃ ; oxazolyl, which is optionally substituted by CH ₃ ; oxadiazolyl, which is optionally substituted by CH ₂ CH ₃ ; thiadiazolyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; 2-pyridyl, which is optionally substituted by Cl, F, CF ₃ , CN, or CONH ₂ ; 3-pyridyl, which is optionally substituted by CF ₃ , CN, CONH ₂ , or CON (CH ₃ ) ₂ substitution; 4-pyridyl, which is optionally substituted with CONH ₂ ; pyrazinyl, which is optionally substituted with CH ₃ ; pyrimidinyl, which is optionally substituted with OCH ₃ ; benzisoxazolyl; And CO (phenyl), where the phenyl is optionally fluorinated. In other embodiments, A is piperazinyl substituted with a third butyl or pyridyl group, where the pyridyl group is optionally substituted with C(O)NH ₂ . In some such embodiments, R is F and n is 1. In some such embodiments, the compound is a compound of formula (II) and R is F. In other such embodiments, the compound is a compound of formula (III) and R is F. In other such embodiments, the compound is of formula (IV), R is F and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F. In other such embodiments, the compound is a compound of formula (VI) and R is F. In other such embodiments, the compound is a compound of formula (VII), R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In other such embodiments, the compound is a compound of formula (IX) and R is F. In some such embodiments, the compound is a compound of formula (II) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (III) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (IV), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (VI) and R is CH ₃ . In other such embodiments, the compound is of formula (VII), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (IX) and R is CH ₃ .

其中R^e 為C_1-6 烷基、SO₂ (C_1-4 烷基)、-(C_0-3 烷基)-(C_3-7 環烷基)、芳基、雜芳基或CO-芳基；其中該烷基、環烷基、芳基或雜芳基為視情況經取代。In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is

Wherein R ^e is C _1-6 alkyl, SO ₂ (C _1-4 alkyl), - (C _0-3 alkyl) - (C _3-7 cycloalkyl), aryl, heteroaryl or CO -Aryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted.

In other embodiments, R ^e is CH _3, CH ₂ CH _3, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, CH ₂ CF _3, CH ( CH ₃ )CF ₃ , SO ₂ CH ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, (CH ₂ )cyclopropyl, (CH ₂ )cyclobutyl, benzene Group, which is optionally substituted by one or more Cl, F, CN, CH ₃ , CONH ₂ ; pyrazolyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; oxazolyl, which is optionally substituted by CH ₃ Or CH ₂ CH ₃ ; oxadiazolyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; thiadiazolyl, which is optionally substituted by CH ₃ , CH ₂ CH ₃ , or CF ₃ ; 2-pyridine Group, 3-pyridyl, or 4-pyridyl, each of which is optionally substituted by Cl, F, CF ₃ , CN, CONH ₂ , CONH(CH ₃ ), or CON(CH ₃ ) ₂ ; Is substituted by CH ₃ or CH ₂ CH ₃ ; pyrimidinyl, which is optionally substituted by OCH ₃ ; benzisoxazolyl; or CO (phenyl), where the phenyl is optionally fluorinated. In some embodiments, R ^e is isopropyl, tertiary butyl, CH(CH ₃ )CF ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, (CH ₂ ) Cyclopropyl and phenyl, which are optionally substituted with one or more Cl, F, CN, CH ₃ , CONH ₂ ; pyrazolyl, which is optionally substituted with CH ₃ ; oxazolyl, which is optionally substituted CH ₃ substitution; oxadiazolyl, which is optionally substituted by CH ₂ CH ₃ ; thiadiazolyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; 2-pyridyl, which is optionally substituted by Cl, F , CF ₃ , CN, or CONH ₂ ; 3-pyridyl, which is optionally substituted by CF ₃ , CN, CONH ₂ , or CON(CH ₃ ) ₂ ; 4-pyridyl, which is optionally substituted by CONH ₂ ; Pyrazinyl, which is optionally substituted by CH ₃ ; pyrimidinyl, which is optionally substituted by OCH ₃ ; benzisoxazolyl; or CO (phenyl), wherein the phenyl is optionally fluorinated. In some such embodiments, R is F or CH ₃ and n is 1. In some such embodiments, the compound is a compound of formula (II) and R is F. In other such embodiments, the compound is a compound of formula (III) and R is F. In other such embodiments, the compound is of formula (IV), R is F and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F. In other such embodiments, the compound is a compound of formula (VI) and R is F. In other such embodiments, the compound is a compound of formula (VII), R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In other such embodiments, the compound is a compound of formula (IX) and R is F. In some such embodiments, the compound is a compound of formula (II) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (III) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (IV), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (VI) and R is CH ₃ . In other such embodiments, the compound is of formula (VII), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (IX) and R is CH ₃ .

In some embodiments of compounds of Formula (I), (IV), or (VII), ring A is morpholinyl, and R is F or CH ₃ , and n is 1. In other embodiments of compounds of formula (II), (III), (V), (VI), (VIII), or (IX), ring A is morpholinyl, and R is F or CH ₃ . In some such embodiments, the compound is a compound of formula (II) and R is F. In other such embodiments, the compound is a compound of formula (III) and R is F. In other such embodiments, the compound is of formula (IV), R is F and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F. In other such embodiments, the compound is a compound of formula (VI) and R is F. In other such embodiments, the compound is a compound of formula (VII), R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In other such embodiments, the compound is a compound of formula (IX) and R is F. In some such embodiments, the compound is a compound of formula (II) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (III) and R is CH ₃ . In other such embodiments, the compound is a compound of formula (IV), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (VI) and R is CH ₃ . In other such embodiments, the compound is of formula (VII), R is CH ₃ and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH ₃ . Also in other such embodiments, the compound is a compound of formula (IX) and R is CH ₃ .

In other embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), ring A is selected from 5-azaspiro[2,3]hexyl; 2-azaspiro[3.3]heptyl; 2-oxa-6-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl; 6-oxa-2-azaspiro[3.4]octyl; 2-azaspiro[3.5]nonyl; 7-oxa-2- Azaspiro[3.5]nonyl; octahydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl; 6-azaspiro[3.4 ]Octyl; 2-oxa-6-azaspiro[3.4]octyl; 6-azaspiro[2.5]octyl; 7-azaspiro[3.5]nonyl; 1-oxa-8-nitrogen Heterospiro[4.5]decyl; 2-oxa-8-azaspiro[4.5]decyl; 2,8-diazaspiro[4.5]dec-1-oneyl; 3-oxa-9-nitrogen Heterospiro[5.5]undecyl; 1,4-oxazoyl; 8-azabicyclo[3.2.1]octyl; and isoindolinyl; each of which is via one or more CH ₃ Or F instead.

In some embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), R is CH ₃ or F. In some embodiments of the compound of formula (I), R is CH ₃ or F. In some embodiments of the compound of formula (II), R is CH ₃ or F. In some embodiments of the compound of formula (III), R is CH ₃ or F. In some embodiments of the compound of formula (IV), R is CH ₃ or F. In some embodiments of the compound of formula (V), R is CH ₃ or F. In some embodiments of the compound of Formula (VI), R is CH ₃ or F. In some embodiments of the compound of Formula (VII), R is CH ₃ or F. In some embodiments of the compound of Formula (VIII), R is CH ₃ or F. In some embodiments of the compound of Formula (IX), R is CH ₃ or F. In some embodiments of the compound of Formula (I), R is CH ₃ . In some embodiments of the compound of Formula (II), R is CH ₃ . In some embodiments of the compound of formula (III), R is CH ₃ . In some embodiments of the compound of formula (IV), R is CH ₃ . In some embodiments of the compound of Formula (V), R is CH ₃ . In some embodiments of the compound of Formula (VI), R is CH ₃ . In some embodiments of the compound of Formula (VII), R is CH ₃ . In some embodiments of the compound of Formula (VIII), R is CH ₃ . In some embodiments of the compound of Formula (IX), R is CH ₃ . In some embodiments of the compound of formula (I), R is F. In some embodiments of the compound of formula (II), R is F. In some embodiments of the compound of formula (III), R is F. In some embodiments of the compound of formula (IV), R is F. In some embodiments of the compound of formula (V), R is F. In some embodiments of the compound of Formula (VI), R is F. In some embodiments of the compound of Formula (VII), R is F. In some embodiments of the compound of Formula (VIII), R is F. In some embodiments of the compound of Formula (IX), R is F.

In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), R is substituted or Unsubstituted C _1-3 alkyl. In one embodiment, R is methyl. In one embodiment, R is ethyl. In one embodiment, R is n-propyl. In one embodiment, R is isopropyl.

In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), R is halogen. In one embodiment, R is F. In one embodiment, R is Cl. In one embodiment, R is Br. In one embodiment, R is I.

In some embodiments of the compound of Formula (I), (IV), or (VII), n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4. In some embodiments of the compound of formula (I), n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4. In some embodiments of the compound of formula (IV), n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4. In some embodiments of the compound of formula (VII), n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4.

In some embodiments of the compound of Formula (I), (IV), or (VII), R is CH ₃ or F and n is 1. In some embodiments of the compound of Formula (I), (IV), or (VII), R is CH ₃ and n is 1. In some embodiments of the compound of Formula (I), (IV), or (VII), R is F and n is 1.

Other embodiments provided herein include combinations of one or more of the above specific embodiments.

Representative compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) are listed in Table 1.

The isoindoline dione compounds listed in Table 1 were tested in the DLBCL analysis described herein and have been found to be active in these compounds. In one embodiment, the isoindoline dione compound is a compound as described herein, wherein the compound grows DLBCL cells at a concentration of 1 μM, for example, SU-DHL-4 cell line growth inhibition is at least about 50% or more many. Method for preparing isoindoline dione compound

流程1Isoindoline dione compounds can be made using conventional organic synthesis and commercially available starting materials. By way of example and not limitation, isoindoline dione compounds of formula (I) can be prepared as outlined in Schemes 1 and 2 shown below and in the examples described herein. It should be noted that those skilled in the art will know how to modify the procedures described in the illustrative processes and examples to obtain the desired products.

Process 1

流程2As shown in Scheme 1, compounds of formula (I) can be prepared, wherein rings A, n and R are as defined herein, the preparation is carried out in solvents such as MeOH, dioxane, DCM, 1,2-dichloroethane , CH ₃ CN, THF or mixtures thereof, in the presence of an acid such as acetic acid or TFA, optionally at a temperature between about 0 ℃ and 25 ℃, using reductive amination agents such as BH ₃ .2- picoline , B ₁₀ H ₁₄ or NaBH(OAc) ₃ , using 3-aminophthalic acid (where R′ is H) or 3-aminophthalic acid dialkyl ester (where R′ is C _1-2 alkyl Group) Reductive amination of 4-hydroxymethylbenzaldehyde (where P ₀ is a hydroxy protecting group) appropriately derivatized and protected starts. In the first method, when R'is H, the intermediate is subjected to treatment with 3-aminopiperidine-2,6-dione and a base such as pyridine at high temperature, for example at about 120°C Cyclization dehydration. Subsequently, the hydroxy protecting group is removed, for example when P _O is a silane ether, P _O can be removed by treatment with an acid such as H ₂ SO ₄ or HCl or a reagent such as TBAF in a solvent such as THF or aqueous THF. In the second method, the protecting group is removed (for example, when R′ is C _1-2 alkyl, for example, by de-protecting the carboxylic acid ester by saponification with a base such as NaOH in a solvent such as aqueous THF, and simultaneously removing the protection Radical P _O , such as silane ether), followed by cyclization dehydration as described above. Subsequently, in a solvent such as DCM, ether or toluene at a temperature between about 0°C and 25°C, a leaving group LG is introduced into the resulting intermediate (where LG is OM, OT or halogen such as Cl or Br), for example when LG When Cl, proceed by reacting with CH ₃ SO ₂ Cl, SOCl ₂ or Ph ₃ P-CCl ₄ or when LG is Br, react by reacting with SOBr ₂ , Ph ₃ P-Br ₂ , or PBr ₃ To proceed, or when LG is OM, by reacting with CH ₃ SO ₂ Cl or methanesulfonic anhydride, or when LG is OT, by reacting with TsCl. In the presence of a base such as DIEA, TEA, Na ₂ CO ₃ , K ₂ CO ₃ , or Cs ₂ CO ₃ in a solvent such as DMSO, DMF, DMA, NMP, or CH ₃ CN at a temperature between about 25°C and 80°C The replacement of the leaving group LG with the ring A as defined herein below provides the target molecule of formula (I).

Process 2

An alternative route for compounds of formula (I) is shown in Scheme 2. The 4-nitroisobenzofuran-1,3-dione is treated with 3-aminopiperidine-2,6-dione in the presence of an acid such as acetic acid at a high temperature, for example 130°C. By in the presence of a catalyst such as Pd/C, Ni or Pt, or Fe or Zn in the presence of HCl, acetic acid or NH ₄ Cl or SnCl ₂ in a solvent such as DMA, EtOH, water, EtOAc, DMF or EtOAc/DMF mixture Treatment with a reducing agent such as hydrogen is used to reduce the nitro group. The amine-containing intermediate is subjected to 4-hydroxyl by appropriate derivatization in the presence of a reducing agent such as B ₁₀ H ₁₄ in a solvent such as MeOH or dioxane or a mixture thereof at a temperature between about 0°C and 25°C Reductive amination performed by the reaction of tolualdehyde. As mentioned previously, then a leaving group LG (LG is OM, OT, Cl or Br) is introduced into the intermediate in a solvent such as dichloromethane, ether or toluene at a temperature between about 0°C and 25°C, For example, when LG is Cl, by reacting with CH ₃ SO ₂ Cl, SOCl ₂ or Ph ₃ P-CCl ₄ , or when LG is Br, by reacting with SOBr ₂ , Ph ₃ P-Br ₂ or PBr _{3 The} reaction proceeds, or when LG is OM, by reacting with CH ₃ SO ₂ Cl or methanesulfonic anhydride, or when LG is OT, by reacting with TsCl. As in Scheme 1, in the presence of a base such as DIEA, TEA, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ in a solvent such as DMSO, DMF, DMA, NMP, or CH ₃ CN at about 25 ° C and The leaving group LG is replaced with a heterocyclic ring A at a temperature between 80°C to provide the target molecule of formula (I).

。In some embodiments, the opposite separation of the mirror image isomers of compounds of formula (I) (by standard methods and as described herein) provides compounds of formula (IV) and compounds of formula (VII)

.

The term "protected" with respect to hydroxyl groups refers to those functional groups that are protected from undesirable reactions by protecting groups known to those skilled in the art, such as protecting groups such as Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY, (5th Edition, 2014) listed in the other, these protective groups can be added or removed using the procedures described therein. Examples of protected hydroxyl groups include, but are not limited to, silane ethers, such as those obtained by the reaction of hydroxyl groups with reagents such as but not limited to: tertiary butyl diphenyl chlorosilane, tertiary butyl dimethyl Chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl ether and ethyl ether, such as but not limited to methoxymethyl ether, methylthiomethyl ether , Benzyloxymethyl ether, third butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropiperanyl ether, 1-ethoxyethyl ether, allyl ether, Benzyl ether; esters, such as benzoate, formate, acetate, trichloroacetate, and trifluoroacetate.

該等方法包含使式(Ia)化合物

， 與

， 在鹼存在下在溶劑中在適於提供式(I)化合物之條件下接觸，其中 環A為視情況經取代之非芳族雜環基(其中連接點處於環氮原子上)； 各R為獨立地經取代或未經取代之C_1-3 烷基、或鹵素； n為0、1、2、3或4；且 LG為OM、OT、或鹵素。In one aspect, provided herein are methods for preparing compounds of formula (I):

These methods include the use of compounds of formula (Ia)

, versus

, Contacted in the presence of a base in a solvent under conditions suitable to provide the compound of formula (I), wherein ring A is optionally substituted non-aromatic heterocyclic group (where the point of attachment is on the ring nitrogen atom); each R Is independently substituted or unsubstituted C _1-3 alkyl, or halogen; n is 0, 1, 2, 3, or 4; and LG is OM, OT, or halogen.

In some embodiments, Ring A is an optionally substituted non-aromatic heterocyclic group selected from the group consisting of: azetidinyl; piperidinyl; piperazinyl; morpholinyl; 5-azaspiro[ 2,3]hexyl; 2-azaspiro[3.3]heptyl; 2-oxa-6-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl; 5-oxa-2 -Azaspiro[3.4]octyl; 6-oxa-2-azaspiro[3.4]octyl; 2-azaspiro[3.5]nonyl; 7-oxa-2-azaspiro[3.5] Nonyl; octahydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl; 6-azaspiro[3.4]octyl; 2- Oxa-6-azaspiro[3.4]octyl; 6-azaspiro[2.5]octyl; 7-azaspiro[3.5]nonyl; 1-oxa-8-azaspiro[4.5]decyl Group; 2-oxa-8-azaspiro[4.5]decyl; 2,8-diazaspiro[4.5]dec-1-one; 3-oxa-9-azaspiro[5.5]dec Monoalkyl; 1,4-oxazo; 8-azabicyclo[3.2.1]octyl; or isoindolinyl. In one embodiment, Ring A is an optionally substituted non-aromatic heterocyclic group selected from the group consisting of: azetidinyl; piperidinyl; piperazinyl; 2-azaspiro[3.3]heptyl ; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl; 7-oxa-2-azaspiro[3.5]nonyl; 1-oxa-8 -Azaspiro[4.5]decyl; or 2,8-diazaspiro[4.5]dec-1-one. In one embodiment, LG is Cl. In another embodiment, LG is Br. In one embodiment, the base is DIEA, TEA, Na ₂ CO ₃ , K ₂ CO ₃ or Cs ₂ CO ₃ . In another embodiment, the solvent is DMSO, DMF, DMA, NMP, or CH ₃ CN. In some embodiments, the contacting is performed at a temperature of about 25°C to about 80°C.

， 該等方法包含使式(Ib)化合物

(a)當LG為Cl時，與CH₃ SO₂ Cl、SOCl₂ 、或Ph₃ P-CCl₄ 接觸； (b)當LG為Br時，與SOBr₂ 、Ph₃ P-Br₂ 、或PBr₃ 接觸； (c)當LG為OM時，與CH₃ SO₂ Cl或甲基磺酸酐接觸； (d)當LG為OT時，與TsCl接觸； 該接觸係在溶劑中在適於提供式(Ia)化合物之條件下進行。In some embodiments, the methods further comprise preparing compounds of formula (Ia):

, The methods include making the compound of formula (Ib)

(a) When LG is Cl, contact with CH ₃ SO ₂ Cl, SOCl ₂ , or Ph ₃ P-CCl ₄ ; (b) When LG is Br, contact with SOBr ₂ , Ph ₃ P-Br ₂ , or PBr ₃ Contact; (c) When LG is OM, contact with CH ₃ SO ₂ Cl or methanesulfonic anhydride; (d) When LG is OT, contact with TsCl; The contact is in a solvent suitable for providing the formula ( Ia) Compound conditions.

In one embodiment, the solvent is DCM, ether or toluene. In some embodiments, the contacting is performed at a temperature of about 0°C to about 25°C.

， 該等方法包含使式(Ic)化合物

在溶劑中在適於提供式(Ib)化合物之條件下脫保護，其中P_O 為羥基保護基。In some embodiments, the methods further comprise preparing compounds of formula (Ib):

, The methods include making the compound of formula (Ic)

Deprotection in a solvent under conditions suitable to provide the compound of formula (Ib), where P _O is a hydroxy protecting group.

In one embodiment, P _O is silicon and alkyl ether is deprotected by treatment with TBAF or with an acid. In some such embodiments, the acid is H ₂ SO ₄ or HCl. In other embodiments, the solvent is THF or aqueous THF. In some embodiments, the deprotection is performed at a temperature of about 0°C to about 60°C.

， 該等方法包含使式(Id)化合物

與3-胺基哌啶-2,6-二酮及鹼在適於提供式(Ic)化合物之條件下接觸，其中R’為H。In some embodiments, the methods further comprise preparing compounds of formula (Ic):

, The methods include making the compound of formula (Id)

Contacting with 3-aminopiperidine-2,6-dione and a base under conditions suitable to provide the compound of formula (Ic), wherein R'is H.

In some embodiments, the base is pyridine. In some embodiments, the contacting is performed at a temperature of about 25°C to about 130°C.

， 該等方法包含使式(Ie)化合物

與3-胺基哌啶-2,6-二酮及鹼在適於提供式(Ib)化合物之條件下接觸。In some other embodiments, the methods further comprise preparing compounds of formula (Ib):

, The methods include making the compound of formula (Ie)

Contact with 3-aminopiperidine-2,6-dione and a base under conditions suitable to provide the compound of formula (Ib).

In some embodiments, the base is pyridine. In some embodiments, the contacting is performed at a temperature of about 25°C to about 120°C.

， 該等方法包含使式(Id)化合物

在適於提供式(Ie)化合物之條件下脫保護，其中R’為C_1-2 烷基且P_O 為羥基保護基。In some such embodiments, the methods further comprise preparing the compound of formula (Ie):

, The methods include making the compound of formula (Id)

Deprotection under conditions suitable to provide compounds of formula (Ie), wherein R'is C _1-2 alkyl and P _O is a hydroxy protecting group.

In one embodiment, P _O is silicon and alkyl ether is deprotected by treatment with a solvent of a base. In one embodiment, the base is NaOH. In another embodiment, the solvent is aqueous THF. In some embodiments, the contacting is performed at a temperature of about 0°C to about 60°C.

， 該等方法包含使式(If)化合物

與式(Ig)化合物

在還原性胺化劑及酸存在下在溶劑中在適於提供式(Id)化合物之條件下接觸，其中R’為H或C_1-2 烷基。In some embodiments, the methods further include preparing a compound of formula (Id):

, The methods include making the compound of formula (If)

With the compound of formula (Ig)

Contacting in the presence of a reductive aminating agent and an acid in a solvent under conditions suitable to provide the compound of formula (Id), where R′ is H or C _1-2 alkyl.

In some embodiments, the reductive amination agent is BH ₃ .2- picoline, B ₁₀ H ₁₄ or NaBH (OAc) _3. In some embodiments, the solvent is MeOH, dioxane, DCM, 1,2-dichloroethane, CH ₃ CN, THF, or a mixture thereof. In other embodiments, the acid is acetic acid or TFA. In some embodiments, the contacting is performed at a temperature of about 0°C to about 25°C.

該等方法包含使式(Ih)化合物

， 與式(Ii)化合物

在還原劑存在下在溶劑中在適於提供式(Ib)化合物之條件下接觸。In some other embodiments, the methods further comprise preparing compounds of formula (Ib):

These methods include the use of compounds of formula (Ih)

, With the compound of formula (Ii)

Contacting in a solvent in the presence of a reducing agent under conditions suitable to provide the compound of formula (Ib).

In one embodiment, the reducing agent is B ₁₀ H ₁₄ . In another embodiment, the solvent is MeOH, dioxane, or a mixture thereof. In some embodiments, the contacting is performed at a temperature of about 0°C to about 25°C.

該等方法包含使式(Ij)化合物

在還原劑存在下在溶劑中在適於提供式(Ih)化合物之條件下還原。In some embodiments, the methods further comprise preparing compounds of formula (Ih):

These methods include the use of compounds of formula (Ij)

Reduction in a solvent in the presence of a reducing agent under conditions suitable to provide the compound of formula (Ih).

In some embodiments, the reducing agent is hydrogen in the presence of a catalyst. In some such embodiments, the catalyst is Pd/C, Ni, or Pt. In other embodiments, the reducing agent is Fe or Zn in the presence of HCl, acetic acid, or NH ₄ Cl. In other embodiments, the reducing agent is SnCl ₂ . In some embodiments, the solvent is DMA, EtOH, water, EtOAc, DMF, or EtOAc/DMF. In some embodiments, the contacting is performed at a temperature of about 0°C to about 60°C. Instructions

Isoindoline dione compounds have utility as drugs for treating, preventing, or ameliorating disease in animals or humans. Therefore, this article provides many uses of isoindoline dione compounds, including the treatment or prevention of the other diseases listed below. The methods provided herein include administering an effective amount of one or more isoindoline dione compounds to an individual in need.

In one aspect, provided herein is a method of treating or preventing DLBCL, which comprises administering to an individual in need thereof an effective amount of an isoindoline dione compound as described herein. One aspect provided herein is a method of treating DLBCL, which comprises administering to an individual in need thereof an effective amount of an isoindolinone compound as described herein. One aspect provided herein is a method of preventing DLBCL, which comprises administering an effective amount of an isoindolinone compound as described herein to an individual in need. For example, isoindoline dione compounds are compounds from Table 1.

Another aspect provided herein is a compound for the treatment or prevention of DLBCL, which includes administering an effective amount of an isoindoline dione compound to an individual in need thereof. In some embodiments, provided herein are compounds for use in the treatment of DLBCL, such treatments comprising administering to an individual in need an effective amount of an isoindoline dione compound as described herein. In some embodiments, provided herein are compounds for preventing DLBCL, which include administering to an individual in need thereof an effective amount of an isoindoline dione compound as described herein. For example, the isoindoline dione compound is a compound from Table 1.

In some embodiments, the DLBCL is activated B cell-like DLBCL (ABC-DLBCL). In other embodiments, the DLBCL is germinal center B cell-like DLBCL (GCB-DLBCL). In other embodiments, the DLBCL is an unclassified DLBCL. In still other embodiments, the DLBCL is a primary mediastinal B cell type DLBCL (PMBL DLBCL). In other embodiments, the DLBCL is a double-strike DLBCL (DHIT DLBCL), also known as cMyc/Bcl-2 mutant DLBCL. In some embodiments, the DLBCL is a triple hit DLBCL (THIT DLBCL), also known as cMyc/Bcl2/Bcl6 rearrangement DLBCL.

In some embodiments, the DLBCL is a newly diagnosed DLBCL. In some embodiments, the DLBCL is primary DLBCL. In other embodiments, the DLBCL is recurrent DLBCL. In other embodiments, the DLBCL is refractory DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL. In some embodiments, the DLBCL is relapsed/refractory DLBCL. In one embodiment, the DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide ( etoposide), bendamustine (Breamustine) (Treanda), lenalidomide (lenalidomide), or gemcitabine (gemcitabine) refractory.

In some embodiments of the methods described herein, the methods further include administration of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine (Treanda), lenalidomide, or one or more of gemcitabine. In some embodiments of the methods described herein, the methods further include administration of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine (Treanda), or one or more of gemcitabine. In some embodiments of the methods described herein, the treatment further includes RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), R-EPOCH (etoposide , Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), stem cell transplantation, bendamustine (Treanda) plus rituximab, rituximab, Lenalidomide plus rituximab, or one or more of the combinations based on gemcitabine. In some embodiments of the methods described herein, the treatment further includes RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), R-EPOCH (etoposide , Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), stem cell transplantation, bendamustine (Treanda) plus rituximab, rituximab, Or treatment based on one or more of the combination of gemcitabine. Pharmaceutical composition and administration route

Isoindoline dione compounds can be administered to individuals orally, topically or parenterally in conventional formulations such as capsules, microcapsules, lozenges, granules, powders, lozenges, pills, suppositories , Injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives such as excipients ( eg , sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, phosphoric acid Calcium or calcium carbonate), binders ( for example , cellulose, methyl cellulose, hydroxymethyl cellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch ), disintegrants ( for example , starch, carboxymethyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricants ( for example, magnesium stearate , Light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring agents ( for example , citric acid, menthol, glycine or orange powder), preservatives ( for example , sodium benzoate, sodium bisulfite, Methyl hydroxybenzoate or propyl paraben), stabilizers ( for example , citric acid, sodium citrate, or acetic acid), suspending agents ( for example , methyl cellulose, polyvinylpyrrolidone, or aluminum stearate) ), dispersing agent ( for example, hydroxypropylmethyl cellulose), diluent ( for example , water), and low wax ( for example, cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the isoindoline dione compound in the pharmaceutical composition may be a level that will achieve the desired effect; for example, in a unit dose for oral and parenteral administration, from about 0.005 mg/kg individual body weight to about 10 mg/kg individual body weight.

The dose of isoindoline dione compound to be administered to an individual varies considerably and can be judged by a health care physician. Generally speaking, the isoindoline dione compound can be administered one to four times daily at a dose of about 0.001 mg/kg individual body weight to about 10 mg/kg individual body weight, but the above dose can be based on the individual's age, weight and medical condition And the type of application and change appropriately. In one embodiment, the dose is about 0.001 mg/kg individual body weight to about 5 mg/kg individual body weight, about 0.01 mg/kg individual body weight to about 5 mg/kg individual body weight, about 0.05 mg/kg individual body weight to about 1 mg/kg individual body weight, about 0.1 mg/kg individual body weight to about 0.75 mg/kg individual body weight or about 0.25 mg/kg individual body weight to about 0.5 mg/kg individual body weight. In one embodiment, one dose is administered daily. In any given case, the amount of isoindoline dione compound administered will depend on many factors, such as the solubility of the active ingredient, the formulation used, and the route of administration.

In another embodiment, provided herein are methods for treating or preventing a disease or condition, the methods comprising administering to an individual in need about 0.01 mg/day to about 750 mg/day, about 0.1 mg/day to about 375 mg/day, about 0.1 mg/day to about 150 mg/day, about 0.1 mg/day to about 75 mg/day, about 0.1 mg/day to about 50 mg/day, about 0.1 mg/day to about 25 mg /Day, or about 0.1 mg/day to about 10 mg/day of isoindoline dione compounds.

In another embodiment, provided herein comprises between about 0.1 mg and 500 mg, between about 1 mg and 250 mg, between about 1 mg and about 100 mg, between about 1 mg and about 50 mg, about 1 Unit dose formulations of isoindoline dione compounds between mg and about 25 mg, or between about 1 mg and about 10 mg.

In a specific embodiment, provided herein is a unit dose formulation comprising about 0.1 mg or 100 mg of an isoindolinone compound.

In another embodiment, provided herein comprises 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 Unit dose formulations of mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg isoindoline dione compounds.

The isoindoline dione compound can be administered once, twice, three times, four times or more times per day. In a specific embodiment, a dose of 100 mg or less is administered as a once daily dose and a dose of more than 100 mg is administered twice daily in an amount equal to half of the total daily dose.

Isoindoline dione compounds can be administered orally for convenience. In one embodiment, when administered orally, the isoindoline dione compound is administered with meal and water. In another embodiment, the isoindoline dione compound is dispersed in a liquid such as water or fruit juice ( eg , apple juice or orange juice) and administered orally as a solution or suspension.

Isoindoline dione compounds can also be intradermal, intramuscular, intraperitoneal, transdermal, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, mucosal, borrow Administer by inhalation, or locally to the ear, nose, eyes, or skin. The mode of administration is determined by the health care physician and may depend in part on the location of the medical condition.

In one embodiment, provided herein are capsules containing an isoindoline dione compound without additional carriers, excipients, or vehicles.

In another embodiment, provided herein is a composition comprising an effective amount of an isoindoline dione compound and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may comprise Excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

The composition may be in the form of lozenges, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories and suspensions, and similar formulations. The composition can be formulated to contain a daily dose or a convenient portion of a daily dose in a dosage unit, which can be a single lozenge or capsule or a convenient volume of liquid. In one embodiment, the solutions are prepared from water-soluble salts such as hydrochloride. In general, all compositions are prepared according to methods known in medicinal chemistry. Capsules can be prepared by mixing the isoindoline dione compound with a suitable carrier or diluent and filling the capsule with an appropriate amount of the mixture. Commonly used carriers and diluents include but are not limited to inert powdered materials, such as many different types of starch, powdered cellulose, especially crystalline cellulose and microcrystalline cellulose; sugars, such as fructose, mannitol and sucrose; cereal flour And similar edible powders.

Lozenges can be prepared by direct compression, by wet granulation, or by dry granulation. The formulations usually incorporate diluents, binders, lubricants and disintegrants as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives can also be used. Typical lozenge binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose, and the like. Natural and synthetic gums are also convenient, including gum arabic, alginate, methyl cellulose, polyvinylpyrrolidine and similar gums. Polyvinyl alcohol, ethyl cellulose and wax can also be used as binders.

Lubricants may be needed in tablet formulations to prevent the tablets and punches from sticking to the dye. The lubricant may be selected from smooth solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Lozenge disintegrants are substances that swell when wet to destroy the lozenge and release the compound. Such disintegrants include starch, clay, cellulose, algae and gum. More specifically, for example, corn and potato starch, methyl cellulose, agar, bentonite, wood cellulose, natural sponge powder, cation exchange resin, alginic acid, guar gum, citrus pomace, and carboxymethyl cellulose and Sodium dodecyl sulfate. The lozenges may be coated with sugar as a flavoring agent and sealant or coated with a film-forming protective agent to adjust the dissolution characteristics of the lozenge. The composition can also be formulated as a chewable tablet, for example, by using a substance such as mannitol in the formulation.

When it is desired to administer the isoindoline dione compound as a suppository, a typical base can be used. Cocoa butter is a traditional suppository base, which can be adjusted by adding wax that slightly raises its melting point. Water-miscible suppository bases specifically containing polyethylene glycols of different molecular weights are widely used.

The effect of isoindoline dione compounds can be delayed or extended by proper formulation. For example, slow-dissolving round pellets of isoindolinodione compounds can be prepared and incorporated into tablets or capsules or incorporated as slow-release implantable devices. The technique also involves making round pellets with several different dissolution rates and filling the capsules with a mixture of these round pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral preparations can be made long-acting by dissolving or suspending the indoline dione compound in an oily or emulsifying vehicle to allow it to be slowly dispersed in the serum. Examples

The following examples are presented by way of illustration, not limitation. Compounds are named using the automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft). With the support of the Cahn-Ingold-Prelog rule of stereochemistry, the tool generates a system name for the chemical structure. Those skilled in the art can modify the procedures described in the illustrative examples to obtain the desired products.

化合物合成實例 1 ： 4-((4-((4-( 第三丁基 ) 哌嗪 -1- 基 ) 甲基 )-3- 甲基苄基 ) 胺基 )-2-(2,6- 二側氧基哌啶 -3- 基 ) 異吲哚啉 -1,3- 二酮

Abbreviations used:

Compound Synthesis Example 1 : 4-((4-((4-( T-butyl ) piperazin- 1 -yl ) methyl )-3 -methylbenzyl ) amino )-2-(2,6- Dioxopiperidin- 3 -yl ) isoindoline- 1,3 -dione

2-(2,6-bi- pendant- 3 -piperidinyl )-4 -nitro - isoindoline- 1,3 -dione : 4-nitroisobenzofuran-1,3- A mixture of dione (70.4 g, 365 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (50.0 g, 304 mmol) in acetic acid (1 L) at 130°C under nitrogen atmosphere Stir for 16 hours. The solvent was removed under reduced pressure and the residual solid was washed with ethyl acetate (500 mL) and dried in vacuo to give 2-(2,6-di-pentoxy-3-piperidinyl)-4- as a gray solid Nitro-isoindoline-1,3-dione (130 g, 70.6% yield). ¹ H NMR (400 MHz DMSO-d ₆ ) δ ppm 11.15 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.09 (t, J = 7.6 Hz, 1H), 5.20-5.15 (m, 1H), 2.89-2.81 (m, 1H), 2.60-2.47 (m, 2H), 2.04 (t, J = 5.6 Hz, 1H).

4-amino-2- (2,6-di-oxo-3-piperidinyl) isoindole-1,3-dione: N ₂ gas layer at a solution of 2- (2,6-di Pendoxy-3-piperidinyl)-4-nitro-isoindoline-1,3-dione (43.0 g, 142 mmol) in DMA (1.5 L) was added Pd/C (15.0 g, 14.1 mmol, 10% Pd). The mixture was degassed under vacuum and purged with H ₂ (3X). The purified mixture was stirred at 40°C for 16 hours under H ₂ atmosphere (40 psi). The reaction mixture was purified with N ₂ , filtered, and the filtrate was concentrated under vacuum. The residual solid was washed with ethyl acetate (200 mL) and dried under vacuum to give 4-amino-2-(2,6-bi- pendoxy-3-piperidinyl)isoindole as a yellow solid Pyridin-1,3-dione (75 g, 64.5% yield). ¹ H NMR (400 MHz DMSO-d ₆ ) δ ppm 11.07 (s, 1H), 7.46 (d, J = 6.4 Hz, 1H), 7.00 (t, J = 7.0 Hz, 2H), 6.51 (br s, 2H ), 5.06-5.01 (m, 1H), 2.93-2.89 (m, 1H), 2.60-2.49 (m, 2H), 2.03-2.00 (m, 1H).

(4-bromo-2-methyl-phenyl) - methoxy - tertiary butyl - diphenyl - Silane: a solution of (4-bromo-2-methyl-phenyl) - methanol (80.0 g, 398 mmol) To a solution in CH ₂ Cl ₂ (800 mL) was added imidazole (32.5 g, 477 mmol), DMAP (2.43 g, 20.0 mmol) and tert-butyl-diphenyl-silyl chloride (164 g, 597 mmol) ). The mixture was stirred at ambient temperature for 16 hours and diluted with saturated ammonium chloride (1.00 L). The mixture was extracted with ethyl acetate (800 mL x 2) and the combined organic fractions were washed with water (600 mL) and saturated NaCl (500 mL). The solution was dried over anhydrous MgSO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether) to give (4-bromo-2-methyl-phenyl)methoxy-tributyl-diphenyl as a pale yellow oil -Silane (147 g, 84.1% yield). ¹ H NMR (400 MHz CDCl ₃ ) δ ppm 7.59 (t, J = 6.4 Hz, 4H), 7.36-7.28 (m, 9H), 4.58 (s, 2H), 2.06 (s, 3H), 1.01(s, 9H).

4- (hydroxymethyl) -3-methyl - benzaldehyde: (4-Bromo-2-methyl-phenyl) - methoxy - tertiary butyl - diphenyl - Silane (147 g, 334 mmol ) The solution in THF (2.0 L) was cooled to -78 °C and n-BuLi (201 mL, 502 mmol, 2.5 M in hexane) was added dropwise while keeping the temperature below -65 °C. After the addition, the reaction mixture was stirred at -65 °C for 30 minutes and DMF (73.4 g, 1.00 mol) was added dropwise, keeping the temperature below -60 °C. The reaction mixture was stirred at this temperature for 2 hours and quenched with saturated NH ₄ Cl (800 mL) below -40°C. Water (800 mL) and ethyl acetate (800 mL) were added and the mixture was stirred for 10 minutes to reach ambient temperature. The organic layer was removed, washed with saturated NaCl (800 mL) and dried over Na ₂ SO ₄ . The solution was filtered and concentrated to give crude 4-[[third butyl(diphenyl)silyl]oxymethyl]-3-methyl-benzaldehyde (130 g) as a light yellow oil, which was not It is used in the next step after any further purification.

TBAF was added to a solution of crude 4-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-methyl-benzaldehyde (130 g, 334 mmol) in THF (2.0 L) -3H ₂ O (52.3 g, 167 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water (800 mL), and extracted with ethyl acetate (500 mL x 2). The organic layers were combined, washed with saturated NaCl (800 mL) and dried over anhydrous Na ₂ SO ₄ . The solution was filtered, concentrated and the residue was purified by silica gel column chromatography (10%-20% petroleum ether/ethyl acetate) to give 4-(hydroxymethyl)-3-methyl as a pale yellow oil -Benzaldehyde (41.0 g, 81.6% yield). ¹ H NMR (400 MHz CDCl ₃ ) δ ppm 9.97 (s, 1H), 7.73-7.60 (m, 3H), 4.78 (s, 2H), 2.38 (s, 3H).

4-((4-( chloromethyl )-3 -methylbenzyl ) amino )-2-(2,6-bi- pendant piperidin- 3 -yl ) isoindoline- 1,3- Diketone : Combine 4-amino-2-(2,6-bi- pendant-3-piperidinyl)isoindoline-1,3-dione (30.0 g, 110 mmol) in 20% MeOH/ The solution in dioxane (725 mL) was cooled to 0°C and 4-(hydroxymethyl)-3-methyl-benzaldehyde (33.0 g, 220 mmol) and B ₁₀ H ₁₄ (26.8 g, 220 mmol) were added sequentially ). The mixture was brought to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated and the residue was treated with EtOH (500 mL). The mixture was stirred for 1 hour, and the resulting slurry was filtered. The collected solid filter cake was washed with ethyl acetate (200 mL) and dried in vacuo to give crude 2-(2,6-di- pendoxypiperidin-3-yl)-4-(( 4-(hydroxymethyl)-3-methylbenzyl)amino)isoindoline-1,3-dione (39.0 g), which was used in the next step without further purification.

2-(2,6-Di-Penoxypiperidin-3-yl)-4-((4-(hydroxymethyl)-3-methylbenzyl)amino)isoindolin-1,3 -A solution of dione (38.0 g, 93.3 mmol) and DIEA (25.3 g, 196 mmol) in NMP (400 mL) was cooled to 0°C and mesyl chloride (21.4 g, 187 mmol) was added over 3 minutes. The ice bath was removed, and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was added dropwise to stirred saturated NaHCO ₃ (800 mL) and washed with water (800 mL). The resulting slurry was filtered, and the product filter cake was dissolved in CH ₂ Cl ₂ (500 mL). The solution was washed with saturated NaCl (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (20%-50% petroleum ether/ethyl acetate). The purified solid was washed with acetonitrile (500 mL) and dried in vacuo to give 4-((4-(chloromethyl)-3-methylbenzyl)amino)-2-(2, 6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (24.0 g, 60.5% yield). ¹ H NMR (400 MHz DMSO-d ₆ ) δ ppm 11.08 (s, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.21-7.16 (m, 3H), 7.00 (d, J = 6.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.07-5.03 (m, 1H), 4.73 (s, 2H), 4.50 (d, J = 6.4 Hz, 2H), 2.87-2.61 (m, 1H), 2.60-2.47 (m, 2H), 2.33 (s, 3H), 2.05-2.04 (m, 1H). LCMS (ESI) m/z 426.2 [M+H] ⁺ .

4-((4-((4-( T-butyl ) piperazin- 1 -yl ) methyl )-3 -methylbenzyl ) amino )-2-(2,6 -bi-sideoxypiper Pyridin- 3 -yl ) isoindoline- 1,3 -dione : 4-((4-(chloromethyl)-3-methylbenzyl)amino)-2-(2,6-di Pendant piperidin-3-yl)isoindoline-1,3-dione (0.075 g, 0.176 mmol), 1-(third butyl) piperazine (0.025 g, 0.176 mmol), and DIEA ( 0.092 mL, 0.528 mmol) was dissolved in DMF (1.0 mL) and the resulting solution was stirred at ambient temperature for 48 hours. The reaction mixture was purified by standard methods to obtain 4-((4-((4-(third (butyl)piperazin-1-yl)methyl)-3-methylbenzyl)amino)-2-( 2,6-Di- pendant piperidin-3-yl)isoindoline-1,3-dione (56.9 mg, 60.8% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.10 (s, 1 H), 8.20 (s, 1 H), 7.52 (dd, J=8.44, 7.21 Hz, 1 H), 7.08-7.20 (m , 4 H), 7.00 (dd, J=17.85, 7.83 Hz, 2 H), 5.07 (dd, J=12.84, 5.26 Hz, 1 H), 4.49 (d, J=6.11 Hz, 2 H), 3.35 ( s, 3 H), 2.84-2.98 (m, 1 H), 2.54-2.63 (m, 2 H), 2.40-2.48 (m, 3 H), 2.32-2.39 (m, 3 H), 2.28 (s, 3 H), 1.96-2.14 (m, 1 H), 0.98 (s, 9 H). LCMS (ESI) m/z 532.4 [M+H] ⁺ . Example 2 : 2-(2,6- Di-Penoxypiperidin- 3 -yl )-4-((3-((4 -ethylpiperidin- 1 -yl ) methyl )-4 -methylbenzyl Group ) Amino group ) Isoindoline- 1,3 -dione hydrochloride

To 4-((4-(chloromethyl)-3-methylbenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3 -DIEA (0.115 mL, 0.657 mmol) was added to a solution of dione (0.080 g, 0.188 mmol) (prepared as described herein) and 4-ethylpiperidine (0.040 g, 0.188 mmol) in anhydrous DMSO (0.30 mL) ) And the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (1.5 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified by standard methods to give 2-(2,6-bi- pendant piperidin-3-yl) -4-((3-((4-ethylpiperidin-1-yl)methyl)-4-methylbenzyl)amino)isoindoline-1,3-dione hydrochloride (56.4 mg, 55.7% yield). LCMS (ESI) m/z 503.6 [M+H] ⁺ . Example 3 : 5-(4-(4-(((2-(2,6- Di- pendoxypiperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl )-2 -methylbenzyl ) piperazin- 1 -yl ) pyridinecarboxamide hydrochloride

To 4-((4-(chloromethyl)-3-methylbenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3 -A solution of dione (0.080 g, 0.188 mmol) (prepared as described herein) and 5-(piperazin-1-yl)pyridinecarboxamide (0.039 g, 0.188 mmol) in anhydrous DMF (0.30 mL) DIEA (0.115 mL, 0.657 mmol) was added and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (1.5 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified by standard methods to give 5-(4-(4-((((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)-2-methylbenzyl)piperazin-1-yl) Pyridinamide hydrochloride (35.0 mg, 29.5% yield). LCMS (ESI) m/z 596.6 [M+H] ⁺ . Example 4 : 4-((4-((6 -azaspiro [2.5] octan -6- yl ) methyl )-3 -methylbenzyl ) amino )-2-(2,6 -bilateral Oxypiperidin- 3 -yl ) isoindoline- 1,3 -dione hydrochloride

To 4-((4-(chloromethyl)-3-methylbenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3 -A solution of dione (0.080 g, 0.188 mmol) and 6-azaspiro[2.5]octane (0.021 g, 0.188 mmol) in anhydrous DMF (0.600 mL) was added DIEA (0.115 mL, 0.657 mmol) and the The reaction mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (1.0 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 4-((4-((6-azaspiro[2.5]octane-6 -Yl)methyl)-3-methylbenzyl)amino)-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3-dione hydrochloride (76.1 mg, 75.3% yield). LCMS (ESI) m/z 501.6 [M+H]+. Example 5 : 2-(2,6- Di- pendant piperidin- 3 -yl )-4-((4-((4- isopropoxypiperidin- 1 -yl ) methyl )-3 -methyl Benzyl ) amino ) isoindolin- 1,3 -dione

To 4-((4-(chloromethyl)-3-methylbenzyl)amino)-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3 -A solution of dione (0.080 g, 0.188 mmol) and 4-isopropoxypiperidine (0.027 g, 0.188 mmol) in anhydrous DMF (0.600 mL) was added DIEA (0.115 mL, 0.657 mmol) and the reaction mixture Stir at ambient temperature for 24 hours. The reaction was diluted with DMSO (1.0 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 2-(2,6-bi- pendant piperidin-3-yl)-4 -((4-((4-isopropoxypiperidin-1-yl)methyl)-3-methylbenzyl)amino)isoindoline-1,3-dione (18.9 mg, 18.8 %). LCMS (ESI) m/z 533.6 [M+H]+. Example 6 : 4-(4-(4-(((2-(2,6- Di- pendant piperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl )-2 -methylbenzyl ) piperazin- 1 -yl )-3 -methylbenzonitrile hydrochloride

To a mixture of 3-methyl-4-piperazin-1-yl-benzonitrile hydrochloride (0.100 g, 0.420 mmol) in DMF (4.0 mL) was added diisopropylethylamine (0.370 mL, 2.10 mmol), followed by addition of 4-((4-(chloromethyl)-3-methylbenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline -1,3-dione (0.179 g, 0.420 mmol). The reaction mixture was stirred at 50 °C for 2 hours, allowed to cool to ambient temperature and diluted with MeOH (1 mL). The mixture was filtered and the filtrate was purified using standard methods to give 4-(4-(4-(((2-(2,6-di-pentoxypiperidin-3-yl)-1,3-di- pendyloxy iso Indolin-4-yl)amino)methyl)-2-methylbenzyl)piperazin-1-yl)-3-methylbenzonitrile hydrochloride (53.0 mg, 18.9% yield). LCMS (ESI) m/z 591.3 [M+1] ⁺ . Example 7 : 5-(4-(4-(((2-(2,6- Di- pendant piperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl ) benzyl ) piperazin- 1 -yl ) pyridinamide

2-(2,6- Di- pendant piperidin- 3 -yl )-4-((4-( hydroxymethyl ) benzyl ) amino ) isoindoline- 1,3 -dione : toward 4 -Amino-2-(2,6-bi- pendant-3-piperidinyl)isoindoline-1,3-dione (25.0 g, 91.5 mmol) in 20% MeOH-dioxane (600 mL) was added 4-(hydroxymethyl)benzaldehyde (25.0 g, 184 mmol) and B ₁₀ H ₁₄ (22.5 g, 184 mmol). The mixture was stirred for 2 hours at ambient temperature under exhaust (pressure) and concentrated. The residue was diluted with ethanol (500 mL) and the mixture was stirred for 1 hour. The resulting suspension was filtered, and the collected solid filter cake was washed with ethyl acetate (200 mL) and dried in vacuo to give crude 2-(2,6-bi- pendyloxypiperidine-3- as a yellow-green solid Group)-4-((4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (28.0 g), which was used in the next step without further purification. LCMS (ESI) m/z 376.2 [MH-18] ⁺ .

4-((4-( chloromethyl ) benzyl ) amino )-2-(2,6-bi- pendant piperidin- 3 -yl ) isoindoline- 1,3 -dione : the crude 2-(2,6-Di- pendant-3-piperidinyl)-4-[[4-(hydroxymethyl)phenyl]methylamino]isoindoline-1,3-dione ( A solution of 28.0 g, 71.2 mmol) and DIEA (26.1 mL, 150 mmol) in NMP (285 mL) was purged with a nitrogen atmosphere and cooled to 0°C. Mesyl chloride (16.3 g, 142 mmol) was added dropwise over 5 minutes and the mixture was allowed to reach ambient temperature. The mixture was stirred at ambient temperature for 16 hours and added dropwise to the stirred saturated NaHCO ₃ (800 mL), diluted with H ₂ O (800 mL). The resulting suspension was filtered, and the collected solid filter cake was washed with H ₂ O (500 mL) and acetonitrile (500 mL). The solid was dried in vacuo to give 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-bi- pendoxypiperidin-3-yl)isoindole as a yellow solid Pyridin-1,3-dione (22.7 g, 77.5% yield). ¹ H NMR (400 MHz DMSO-d ₆ ) δ ppm 11.12 (s, 1H), 7.51-7.28 (m, 6H), 7.03 (d, J = 6.8 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.11-5.06 (m, 1H), 4.74 (s, 2H), 4.58 (d, J = 6.0 Hz, 2H), 2.94-2.86 (m, 1H), 2.63-2.51 (m, 2H), 2.08 -2.05 (m, 1H). LCMS (ESI) m/z 412.1 [M+H] ⁺ .

5-(4-(4-(((2-(2,6- Di-Penoxypiperidin- 3 -yl )-1,3 -Di-Penoxyisoindolin- 4 -yl ) amino ) Methyl ) benzyl ) piperazin- 1 -yl ) pyridinecarboxamide : to 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-bi- pendant piperidine -3-yl)isoindoline-1,3-dione (300 mg, 0.619 mmol) in anhydrous DMSO (3.0 mL) was added 5-(piperazin-1-yl)pyridinecarboxamide sequentially (153 mg, 0.743 mmol) and DIEA (108 µL, 0.619 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and diluted with 15% formic acid in DMSO (3 mL). The mixture was filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to provide 5-(4-(4-(((2-(2,6-di-sideoxypiperidin-3-yl)- 1,3-Di- pendant isoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)pyridinecarboxamide (255 mg, 70.8%). LCMS (ESI) m/z 582.2 [M+H] ⁺ . Example 8 : 4-(1-(4-(((2-(2,6- Di-pentoxypiperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl ) benzyl ) azetidin- 3 -yl ) benzonitrile hydrochloride

To 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3-dione (0.062 g, 0.150 mmol) and 4-(azetidin-3-yl)benzonitrile hydrochloride (0.031 g, 0.180 mmol) in anhydrous DMF (0.30 mL) was added DIEA (0.079 mL, 0.450 mmol) and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was quenched with cooled 10% formic acid in DMSO (1.5 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 4-(1-(4-(((2 -(2,6-bi- pendant piperidin-3-yl)-1,3-bi- pendant isoindolin-4-yl)amino)methyl)benzyl)azetidine- 3-yl)benzonitrile hydrochloride (31.0 mg, 36.3% yield). LCMS (ESI) m/z 534.2 [M+H] ⁺ . Example 9 : 2-(2,6- Di-Penoxypiperidin- 3 -yl )-4-((4-((4-(5- fluoropyridin -2- yl ) piperazin- 1 -yl ) methan Group ) benzyl ) amino group ) isoindoline- 1,3 -dione

4-((4-(chloromethyl)benzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (0.20 g, 0.487 mmol), DIEA (0.296 mL, 1.70 mmol), and a mixture of 1-(5-fluoro-2-pyridyl)piperazine (153.7 mg, 0.848 mmol) in DMF (3.00 mL) at 50°C Stir for 24 hours under N ₂ atmosphere. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with saturated sodium chloride (3×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification of the residue by standard methods gave 2-(2,6-bi- pendant piperidin-3-yl)-4-((4-((4-(5-fluoropyridin-2-yl)piperazine -1-yl)methyl)benzyl)amino)isoindoline-1,3-dione hydrochloride (238 mg, 97.6% yield). LCMS (ESI) m/z 557.3 [M+H] ⁺ . Example 10 : 6-(4-(4-(((2-(2,6- Di- pendant piperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl ) benzyl ) piperazin- 1 -yl ) nicotinamide

4-((4-(chloromethyl)benzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (0.216 g, 0.524 mmol), 6-(piperazin-1-yl) nicotinamide (0.108 g, 0.524 mmol), and DIEA (0.275 mL, 1.57 mmol) were dissolved in DMF (2.9 mL) and the mixture was at ambient temperature Stir for 16 hours. The mixture was purified using standard methods to obtain 6-(4-(4-(((2-(2,6-di-sideoxypiperidin-3-yl)-1,3-bi-sideoxyisoindoline- 4-yl)amino)methyl)benzyl)piperazin-1-yl)nicotinamide (125 mg, 41.0% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.10 (s, 1 H), 8.59 (d, J=2.20 Hz, 1 H), 7.94 (dd, J=9.05, 2.45 Hz, 1 H), 7.74 (br d, J=1.96 Hz, 1 H), 7.44-7.56 (m, 1 H), 7.32 (q, J=8.23 Hz, 4 H), 7.20 (br t, J=6.24 Hz, 1 H) , 7.05-7.15 (m, 1 H), 7.00 (dd, J=15.65, 7.83 Hz, 2 H), 6.80 (d, J=9.05 Hz, 1 H), 5.07 (dd, J=12.84, 5.26 Hz, 1 H), 4.55 (br d, J=6.36 Hz, 2 H), 3.56 (br d, J=4.65 Hz, 4 H), 3.48 (s, 2 H), 2.81-2.99 (m, 1 H), 2.54-2.64 (m, 2 H), 2.42 (br t, J=4.77 Hz, 4 H), 1.96-2.10 (m, 1 H). LCMS (ESI) m/z 582.2 [M+H] ⁺ . Example 11 : 5-(4-(4-(((2-(2,6- Di- pendant piperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl ) benzyl ) piperazin- 1 -yl )-N,N -dimethylpyridinecarboxamide

4-((4-(chloromethyl)benzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (0.450 g, 1.09 mmol), N,N-dimethyl-5-(piperazin-1-yl)pyridinecarboxamide hydrochloride (0.444 g, 1.64 mmol), and DIEA (0.954 mL, 5.46 mmol) were dissolved in DMF (6.0 mL) and the mixture was stirred at ambient temperature for 72 hours. The mixture was purified using standard methods to give 5-(4-(4-(((2-(2,6-di-side-piperidin-3-yl)-1,3-di-side-oxyisoindoline- 4-yl)amino)methyl)benzyl)piperazin-1-yl)-N,N-dimethylpyridinecarboxamide (177 mg, 26.6% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.10 (s, 1 H), 8.22 (br d, J=1.96 Hz, 1 H), 7.42-7.59 (m, 2 H), 7.27-7.39 ( m, 5 H), 7.21 (br t, J=5.62 Hz, 1 H), 7.00 (br dd, J=15.53, 7.70 Hz, 2 H), 5.07 (br dd, J=12.59, 5.01 Hz, 1 H ), 4.55 (br d, J=5.87 Hz, 2 H), 3.50 (s, 2 H), 3.27 (br s, 4 H), 2.80-3.10 (m, 7 H), 2.54-2.64 (m, 2 H), 2.39-2.48 (m, 4 H), 2.05 (br dd, J=10.51, 4.89 Hz, 1 H). LCMS (ESI) m/z 610.4 [M+H] ⁺ . Example 12 : 4-((4-((4-(1H- pyrazol- 1 -yl ) piperidin- 1 -yl ) methyl ) benzyl ) amino )-2-(2,6 -dioxy Piperidin- 3 -yl ) isoindoline- 1,3 -dione hydrochloride

To 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3-dione (0.200 g, 0.486 mmol) and 4-(1H-pyrazol-1-yl)piperidine (0.073 g, 0.486 mmol) in anhydrous DMF (1.50 mL), DIEA (0.297 mL, 1.70 mmol) was added and the reaction The mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (2.0 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 4-((4-((4-(1H-pyrazol-1-yl) Piperidin-1-yl)methyl)benzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione hydrochloride ( 69.9 mg, 25.6%). LCMS (ESI) m/z 527.6 [M+H] ⁺ . Example 13 : 4-(4-(4-(((2-(2,6- Di- pendant piperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) amino) methyl) benzyl) piperazin-1-yl) benzoyl amine

4-((4-(chloromethyl)benzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (0.075 g, 0.182 mmol), 4-(piperazin-1-yl)benzamide hydrochloride (0.044 g, 0.182 mmol), and DIEA (0.127 mL, 0.728 mmol) were dissolved in DMF (1.0 mL) and the The resulting solution was stirred at ambient temperature for 16 hours. The reaction was stirred at 50 °C for an additional 5 hours and cooled to ambient temperature. The mixture was purified using standard methods to obtain 4-(4-(4-(((2-(2,6-di-sideoxypiperidin-3-yl)-1,3-bi-sideoxyisoindoline- 4-yl)amino)methyl)benzyl)piperazin-1-yl)benzamide (71.4 mg, 67.5% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.11 (s, 1 H), 7.65-7.79 (m, 3 H), 7.52 (t, J=7.83 Hz, 1 H), 7.27-7.40 (m , 4 H), 7.21 (br t, J=6.36 Hz, 1 H), 7.01 (dd, J=15.65, 7.82 Hz, 3 H), 6.91 (d, J=8.80 Hz, 2 H), 5.08 (dd , J=12.96, 5.38 Hz, 1 H), 4.56 (br d, J=6.36 Hz, 2 H), 3.49 (s, 2 H), 3.23 (br s, 4 H), 2.84-2.96 (m, 1 H), 2.55 (s, 2 H), 2.48 (br s, 4 H), 2.06 (br dd, J=10.64, 5.50 Hz, 1 H). LCMS (ESI) m/z 581.4 [M+H] ⁺ . Example 14: (S) -6- (4- (4 - (((2- (2,6- two-oxo-piperidin-3-yl) -1,3-isoindoline-oxo - 4- yl ) amino ) methyl ) benzyl ) piperazin- 1 -yl ) nicotinamide

(S)-2-(2,6 -Dipentoxypiperidin- 3 -yl )-4-((4-( hydroxymethyl ) benzyl ) amino ) isoindoline- 1,3 -di Ketone : (S)-4-amino-2-(2,6-di-pentoxypiperidin-3-yl)isoindoline-1,3-dione (1.37 g, 5.00 mmol) (eg U.S. Patent Publication US 2007/0004920 (prepared as described) and a suspension of 4-(hydroxymethyl)benzaldehyde (0.817 g, 6.00 mmol) in anhydrous 2:1 dioxane-MeOH (25 mL) cooled to 0 Decane borane (1.34 g, 9.90 mmol) was added in small portions at 2°C over 2 minutes. Equip the reaction flask with a septum and pinhole and stir the mixture vigorously for 10 minutes. The resulting solution was brought to ambient temperature and stirred for 3 hours. The mixture was concentrated and the residual yellow foam was purified on a silica gel column (Biotage KP-Sil 50 g, 0-10% MeOH-CH ₂ Cl ₂ gradient). The product was suspended in MTBE (75 mL) and stirred vigorously for 16 hours. The suspension was collected, washed with MTBE and dried in vacuo to provide (S)-2-(2,6-bi-sideoxypiperidin-3-yl)-4-((4-(hydroxymethyl )Benzyl)amino)isoindoline-1,3-dione (1.82 g, 93% yield). LCMS (ESI) m/z 394.0 [M+H] ⁺ .

(S)-4-((4-( chloromethyl ) benzyl ) amino )-2-(2,6-bi- pendant piperidin- 3 -yl ) isoindoline- 1,3 -di Ketone : (S)-2-(2,6-bi- pendant piperidin-3-yl)-4-((4-(hydroxymethyl)benzyl)amino)isoindolin-1, A solution of 3-dione (1.50 g, 3.81 mmol) in anhydrous NMP (12 mL) was cooled to 0°C and mesyl chloride (0.594 mL, 7.63 mmol) and DIEA (1.33 mL, 7.63 mmol) were added in sequence. The mixture was stirred for 7 hours, during which the temperature slowly reached the ambient temperature over 2 hours. Additional mesyl chloride (0.120 mL) and DIEA (0.260 mL) were added and the mixture was stirred for 15 hours. The reaction mixture was slowly added to H ₂ O (60 mL), cooled to 0 °C while mixing vigorously. The resulting yellow slurry was stirred for 10 minutes and the precipitate was collected by vacuum filtration. The collected solid was washed with H ₂ O and Et ₂ O and dissolved in EtOAc. The solution was dried over MgSO ₄ , filtered and concentrated to give crude (S)-4-((4-(chloromethyl)benzyl)amino)-2-(2,6-side) as a yellow solid Oxypiperidin-3-yl)isoindoline-1,3-dione, which was used in the next step without further purification. LCMS (ESI) m/z 412.0 [M+H] ⁺ .

(S)-6-(4-(4-(((2-(2,6- Di-pentoxypiperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl ) benzyl ) piperazin- 1 -yl ) nicotinamide : To (S)-4-((4-(chloromethyl)benzyl)amino)-2-(2,6 -Di- pendant piperidin-3-yl)isoindoline-1,3-dione (242 mg, 0.500 mmol) in anhydrous DMSO (1.5 mL) was added 6-(piperazine-1- Base) nicotinamide (113 mg, 0.550 mmol) and the mixture was stirred for 15 minutes. DIEA (0.087 mL, 0.500 mmol) was added to the resulting solution and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with 20% formic acid in DMSO (3 mL) and filtered (nylon, 45 μm). Purify the solution by standard methods to obtain (S)-6-(4-(4-(((2-(2,6-bi-sideoxypiperidin-3-yl)-1,3-bi-side oxygen Isoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)nicotinamide (156 mg, 54%). LCMS (ESI) m/z 582.2 [M+H] ⁺ . 88% ee was obtained by palm HPLC. Example 15: (R) -6- (4- (4 - (((2- (2,6- two-oxo-piperidin-3-yl) -1,3-isoindoline-oxo - 4- yl ) amino ) methyl ) benzyl ) piperazin- 1 -yl ) nicotinamide

By further purifying the material obtained in Example 14 by palm-phase reverse phase chromatography, (S)-6-(4-(4-(((2-(2,6-di-sideoxypiperidine- 3-yl)-1,3-bi- pendant isoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)nicotinamide (119 mg, >99% ee) , LCMS (ESI) m/z 582.2 [M+H] ⁺ , and (R)-6-(4-(4-(((2-(2,6-dipentoxypiperidin-3-yl) -1,3-bi- pendant isoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)nicotinamide (6 mg, >99% ee), LCMS (ESI ) m/z 582.2 [M+H] ⁺ . Example 16 : 4-(4-(4-(((2-(2,6- Di-pentoxypiperidin- 3 -yl )-1,3 -bi- pendant isoindolin- 4 -yl ) Amino ) methyl ) benzyl ) piperazin- 1 -yl ) pyridinamide

To 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3-dione (0.080 g, 0.194 mmol) and 6-(piperazin-1-yl)pyridinecarboxamide (0.040 g, 0.188 mmol) in anhydrous DMSO (0.30 mL) was added DIEA (0.102 mL, 0.583 mmol) and the reaction The mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (1.5 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 6-(4-(4-((((2-(2,6-side Oxypiperidin-3-yl)-1,3-bi- pendant isoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)pyridinamide (41.0 mg , 36.3% yield). LCMS (ESI) m/z 582.6 [M+H] ⁺ . Example 17 : 2-(2,6- Di-Penoxypiperidin- 3 -yl )-4-((4-((4 -ethylpiperidin- 1 -yl ) methyl ) benzyl ) amino ) Isoindoline- 1,3 -dione hydrochloride

To 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3-dione (0.200 g, 0.486 mmol) and 4-ethylpiperidine (0.055 g, 0.486 mmol) in anhydrous DMF (1.50 mL) was added DIEA (0.297 mL, 1.70 mmol) and the reaction mixture was stirred at ambient temperature for 24 hours . The reaction was diluted with DMSO (2.0 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 2-(2,6-bi- pendant piperidin-3-yl)-4 -((4-((4-ethylpiperidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione hydrochloride (127.4 mg, 50.0% yield) . LCMS (ESI) m/z 489.6 [M+H] ⁺ . Example 18 : 4-((4-((2 -azaspiro [3.3] heptan- 2- yl ) methyl )-2- fluorobenzyl ) amino )-2-(2,6 -dioxy Piperidin- 3 -yl ) isoindoline- 1,3 -dione

(4- Bromo- 3- fluorophenyl ) methanol : A solution of 4-bromo-3-fluoro-benzoic acid (15.0 g, 68.5 mmol) in THF (150 mL) was cooled to 0°C and the reaction was carried out under a nitrogen atmosphere. Borane-dimethyl sulfide complex (13.7 mL, 137 mmol, 10 M in THF) was added dropwise. The cooling bath was removed and the mixture was stirred at ambient temperature for 12 hours. The mixture was cooled to 0 °C, quenched with MeOH (50 mL) and poured into water (30 mL). The mixture was concentrated under vacuum and the residual aqueous mixture was diluted with ethyl acetate (150 mL) and water (150 mL) and stirred for 15 minutes. The organic phase was removed and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The organic fractions were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (2%-10% ethyl acetate in petroleum ether) to give 4-bromo-3-fluoro-phenyl)methanol (13.1 g, 93.3%) as a colorless liquid Yield). LCMS (ESI) m/z 187.0 [MH-18 ⁺ ]. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.54-7.45 (m, 1H), 7.14 (d, J = 9.2 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 4.64 (d, J = 4.6 Hz, 2H), 2.20 (br s, 1H).

(4-bromo-3-fluoro-phenyl) - methoxy - tertiary butyl - dimethyl - Silane: (4-Bromo-3-fluoro-phenyl) - methanol (13.1 g, 63.9 mmol) and imidazole (12.2 g, 179 mmol) in DMF (150 mL) in the solution was cooled to 0 ℃ and tertiary butyl chloride was added dimethyl Silane (14.4 g, 95.8 mmol). The cooling bath was removed and the mixture was stirred at ambient temperature for 16 hours. The reaction was poured into cooled water (30 mL), diluted with ethyl acetate (100 mL) and water (100 mL), and stirred for 15 minutes. The organic phase was removed and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The organic fractions were combined, washed with saturated NaCl (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give (4-bromo-3-fluoro-phenyl)methoxy- third butyl as a colorless liquid -Dimethyl-silane (18.6 g, 91.2% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.49 (dd, J = 7.1, 8.1 Hz, 1H), 7.18-7.08 (m, 1H), 7.01-6.92 (m, 1H), 4.69 (s, 2H) , 0.96 (s, 9H), 0.12 (s, 6H).

4 - [[tert-butyl (dimethyl) silicone alkyl] oxymethyl] -2-fluoro - benzaldehyde: Under a nitrogen atmosphere, (4-bromo-3-fluoro-phenyl) - methoxy -A solution of tert-butyl-dimethyl-silane (18.6 g, 58.3 mmol) in THF (150 mL) was cooled to -78°C and n-BuLi (25.6 mL, 64.0 mmol, in hexane) was added dropwise 2.5 M). The mixture was stirred at -78 °C for 5 minutes, and DMF (5.83 mL, 75.7 mmol) was added. The mixture was stirred at -78°C for 2 hours and allowed to warm to ambient temperature. The reaction mixture was cooled to 0 °C and quenched with saturated ammonium chloride (60 mL) and water (30 mL). The mixture was quenched with ethyl acetate (2 x 150 mL) and the combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-2% ethyl acetate in petroleum ether) to give 4-[[ third butyl(dimethyl)silyl]oxymethyl as a yellow liquid Yl]-2-fluoro-benzaldehyde (11.5 g, 73.5% yield). MS (ESI) m/z : 269.1 [M+1] ⁺ .

3-((4-((( third butyldimethylsilyl ) oxy ) methyl )-2- fluorobenzyl ) amino ) phthalic acid: convert 4-[[ third butyl( Dimethyl)silyl]oxymethyl]-2-fluoro-benzaldehyde (7.50 g, 27.9 mmol) and 3-aminophthalic acid (5.06 g, 27.9 mmol) in 1:10 acetic acid-MeOH ( The solution in 110 mL) was stirred at 25°C for 30 minutes and cooled to 0°C. Borane 2-picoline complex (4.48 g, 41.9 mmol) was added and the mixture was brought to ambient temperature. The mixture was stirred at ambient temperature for 16 hours and the mixture was concentrated under reduced pressure. The residue was diluted with water (25 mL) and ethyl acetate (25 mL) and stirred for 15 minutes. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The organic fractions were combined, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (2%-5% ethyl acetate in petroleum ether) to give 3-((4-(((third butyldimethylsilyl )Oxy)methyl)-2-fluorobenzyl)amino)phthalic acid (9.90 g, 81.8% yield). LCMS (ESI) m/z : 434.1 [M+1] ⁺ .

4 - ((4 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) -2-fluorobenzyl) amino) -2- (2,6-oxo-piperidin - 3- yl ) isoindoline- 1,3 -dione : 3-((4-(((third butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amine Base) phthalic acid (11.8 g, 27.2 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (6.72 g, 40.8 mmol) in pyridine (150 mL) at 120°C Stir for 12 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (2%-5% ethyl acetate in petroleum ether) to give 4-((4-(((third butyl Dimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3 -Diketone (9.90 g, 69.2% yield). LCMS (ESI) m/z : 526.2 [M+1] ⁺ .

2-(2,6- Di-Penoxypiperidin- 3 -yl )-4-((2- fluoro- 4-( hydroxymethyl ) benzyl ) amino ) isoindoline- 1,3 -di Ketone : To 4-((4-(((third butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)-2-(2,6-bi- pendant Piperidin-3-yl)isoindoline-1,3-dione (9.90 g, 18.8 mmol) in THF (100 mL) was added concentrated sulfuric acid (20.0 mL, 368 mmol) and the mixture was added Stir at ambient temperature for 12 hours. The mixture was concentrated under vacuum and the residue was treated with 1:5 ethyl acetate-petroleum ether (20 mL). The resulting suspension was stirred for 30 minutes and filtered. The collected solid was washed with 1:5 ethyl acetate-petroleum ether and dried in vacuo to give 2-(2,6-bi- pendoxypiperidin-3-yl)-4-((2- Fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (6.58 g, 85.2% yield). MS (ESI) m/z : 412.0 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.12 (s, 1H), 7.54 (dd, J = 7.3, 8.4 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.16-7.07 (m, 3H), 7.05 (d, J = 7.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 5.33-5.25 (m, 1H), 5.07 (dd, J = 5.3, 12.9 Hz, 1H), 4.59 (d, J = 6.3 Hz, 2H), 4.47 (d, J = 5.8 Hz, 2H), 2.95-2.84 (m, 1H), 2.65-2.52 (m, 2H), 2.09-2.01 (m , 1H).

4-((4-( chloromethyl )-2- fluorobenzyl ) amino )-2-(2,6-bi- pendant piperidin- 3 -yl ) isoindoline- 1,3 -di Ketone : 2-(2,6-bi- pendant piperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindolin-1, A solution of 3-diketone (6.58 g, 16.0 mmol) in dichloromethane (200 mL) was cooled to 0 °C and sulfenyl chloride (20.0 mL, 276 mmol) was added dropwise. After the addition was completed, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (1.00%-1.25% MeOH in dichloromethane) to give 4-((4-(chloromethyl)-2 as a yellow solid -Fluorobenzyl)amino)-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3-dione (3.80 g, 55.4% yield). LCMS (ESI) m/z : 430.0 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.12 (s, 1H), 7.54 (dd, J = 7.3, 8.4 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32 (dd , J = 1.5, 11.0 Hz, 1H), 7.24 (dd, J = 1.6, 7.8 Hz, 1H), 7.16 (t, J = 6.3 Hz, 1H), 7.06 (d, J = 6.9 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 5.08 (dd, J = 5.3, 12.9 Hz, 1H), 4.74 (s, 2H), 4.63 (d, J = 6.3 Hz, 2H), 2.95-2.85 (m, 1H), 2.66-2.53 (m, 2H), 2.09-2.02 (m, 1H).

4-((4-((2 -azaspiro [3.3] heptan- 2- yl ) methyl )-2- fluorobenzyl ) amino )-2-(2,6-bi- pendant piperidine -3 -yl ) isoindoline- 1,3 -dione : 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxy Piperidin-3-yl)isoindoline-1,3-dione (0.200 g, 0.486 mmol) and 2-azaspiro[3.3]heptane (0.132 g, 0.931 mmol) in anhydrous DMF (1.00 mL ) Was added DIEA (0.284 mL, 1.63 mmol) and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (2.0 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 2-(2,6-bi- pendant piperidin-3-yl)-4 -((4-((4-ethylpiperidin-yl)methyl)benzyl)amino)isoindoline-1,3-dione (18.6 mg, 8.2% yield). LCMS (ESI) m/z 491.5 [M+H] ⁺ . Example 19 : 2-(2,6- Di-Penoxypiperidin- 3 -yl )-4-((2- fluoro -4-((3- morpholinylazetidin- 1 -yl ) methyl Group ) benzyl ) amino group ) isoindoline- 1,3 -dione

To 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3- Diketone (215 mg, 0.500 mmol) (prepared as described herein) and 4-(azetidin-3-yl)morpholine hydrochloride (107 mg, 0.600 mmol) in anhydrous DMSO (1.7 mL) DIEA (262 µL, 1.50 mmol) was added to the solution and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was diluted with 20% formic acid in DMSO (2.5 mL) and filtered through a membrane syringe filter (45 μm nylon). The solution was purified using standard methods to provide 2-(2,6-bi- pendant piperidin-3-yl)-4-((2-fluoro-4-((3-morpholinylazetidine-1 -Yl)methyl)benzyl)amino)isoindoline-1,3-dione (173 mg, 64.6% yield). LCMS (ESI) m/z 536.2 [M+H]+. Example 20 : 6-(4-(4-(((2-(2,6- Di- pendant piperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl )-3- fluorobenzyl ) piperazin- 1 -yl ) nicotinamide

To 4-((4-(chloromethyl)-3-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3- DIEA (0.12 mL, 0.698 mmol) was added to a solution of dione (60.0 mg, 0.140 mmol) and 6-(piperazin-1-yl) nicotinamide (35.0 mg, 0.168 mmol) in anhydrous DMSO (1.0 mL). And the reaction mixture was stirred at 60°C for 5 hours. The reaction was quenched with 10% formic acid in DMSO (1.0 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 6-(4-(4-(((2-( 2,6-Di- pendant piperidin-3-yl)-1,3-di- pendant isoindolin-4-yl)amino)methyl)-3-fluorobenzyl)piperazine-1 -Yl) nicotinamide (69.0 mg, 82% yield). LCMS (ESI) m/z 600.2 [M+H]+. Example 21 : 2-(2,6- Di- pendant piperidin- 3 -yl )-4-((4-((4-( ethylsulfonyl ) piperidin- 1 -yl ) methyl )- 2- fluorobenzyl ) amino ) isoindoline- 1,3 -dione

To 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3- DIEA (105 µL, 0.600 mmol) was added to a mixture of dione (64.5 mg, 0.150 mmol) and 4-(ethylsulfonyl)piperidine hydrochloride (38.5 mg, 0.180 mmol) in anhydrous DMSO (0.5 mL). ) And the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with 20% formic acid in DMSO (1 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified by standard methods to give 2-(2,6-bi- pendoxy piperidine-3 -Yl)-4-((4-((4-(ethylsulfonyl)piperidin-1-yl)methyl)-2-fluorobenzyl)amino)isoindoline-1,3- Dione (58.0 mg, 67.8% yield). LCMS (ESI) m/z 571.4 [M+H]+. Example 22 : 2-(2,6- Di- pendant piperidin- 3 -yl )-4-((2- fluoro -4-((3-( pyridin -2- yl ) azetidine- 1 - yl) methyl) benzyl) amino) isoindoline-1,3-dione

To 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3- A mixture of dione (64.5 mg, 0.150 mmol) and 2-(azetidin-3-yl)pyridine dihydrochloride (46.6 mg, 0.225 mmol) in anhydrous DMSO (0.5 mL) was added DIEA (105 µL, 0.600 mmol) and the reaction mixture was stirred at ambient temperature for 7 hours. The mixture was diluted with 20% formic acid in DMSO (1 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified by standard methods to give 2-(2,6-bi- pendant piperidine-3 -Yl)-4-((2-fluoro-4-((3-(pyridin-2-yl)azetidin-1-yl)methyl)benzyl)amino)isoindolin-1 , 3-diketone (34.0 mg, 43.0% yield). LCMS (ESI) m/z 528.2 [M+H]+. Example 23 : 2-(2,6 -Dioxopiperidin- 3 -yl )-4-((2- fluoro -4-((3-(2 -oxopyrrolidin- 1 -yl ) nitrogen Heterocyclobutan- 1 -yl ) methyl ) benzyl ) amino ) isoindoline- 1,3 -dione

To 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3- Dione (64.5 mg, 0.150 mmol) and 1-(azetidin-3-yl)pyrrolidin-2-one trifluoroacetate (57.2 mg, 0.225 mmol) in anhydrous DMSO (0.5 mL) DIEA (105 µL, 0.600 mmol) was added to the mixture and the reaction mixture was stirred at ambient temperature for 24 hours. The mixture was diluted with 20% formic acid in DMSO (1 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 2-(2,6-bi- pendyloxypiperidine-3- Yl)-4-((2-fluoro-4-((3-(2-oxopyrrolidin-1-yl)azetidin-1-yl)methyl)benzyl)amino)iso Indoline-1,3-dione (35.0 mg, 43.7% yield). LCMS (ESI) m/z 534.2 [M+H]+. Example 24 : 2-(2,6- Di-Penoxypiperidin- 3 -yl )-4-((3- fluoro -4-((4- isopropylpiperidin- 1 -yl ) methyl ) benzyl Group ) amino group ) isoindoline- 1,3 -dione

((4- Bromo -2- fluorobenzyl ) oxy ) ( third butyl ) dimethyl silane: (4-bromo-2-fluorophenyl) methanol (30.0 g, 146 mmol) and imidazole (14.9 g, 219 mmol) in dichloromethane (200 mL) was cooled to 0°C and third butyl-chlorodimethylsilane (24.2 g, 161 mmol) was added. The mixture was stirred for 5 minutes, the cooling bath was removed and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into cooled water (300 mL), mixed and the organic layer was separated. The aqueous layer was extracted with dichloromethane (30 mL x 3) and the combined organic layers were washed with saturated NaCl (20 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow color Oily ((4-bromo-2-fluorobenzyl)oxy) (third butyl) dimethylsilane (46.0 g, 98.5%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.40-7.34 (m, 1H), 7.31-7.28 (m, 1H), 7.19 (dd, J = 1.8, 9.6 Hz, 1H), 4.74 (s, 2H) , 0.97 (s, 9H), 0.16 (s, 6H).

4-((( Third-butyldimethylsilyl ) oxy ) methyl )-3- fluorobenzaldehyde: Under a nitrogen atmosphere, convert ((4-bromo-2-fluorobenzyl)oxy)( A solution of tert-butyl)dimethylsilane (10.0 g, 31.3 mmol) in THF (30 mL) was cooled to -78°C and n-butyllithium (15.0 mL, 37.5 mmol, 2.5 M in hexane) was added . The mixture was stirred at -78 °C for 2 hours and DMF (3.61 mL, 47.0 mmol) was added. The mixture was brought to ambient temperature and stirred for 30 minutes. The reaction mixture was cooled to 0 °C and quenched with saturated ammonium chloride (15 mL) and diluted with water (30 mL). The mixture was extracted with ethyl acetate (40 mL x 3) and the combined organic layer was washed with saturated NaCl (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The crude 4-(((third butyldimethylsilyl)oxy)methyl)-3-fluorobenzaldehyde (8.00 g, 95.4% yield). LCMS (ESI) m/z : 269.0 [M+1] ⁺ .

3-((4-((( T-butyldimethylsilyl ) oxy ) methyl )-3- fluorobenzyl ) amino ) dimethyl phthalate : the crude 4-((( Tert-Butyldimethylsilyl)oxy)methyl)-3-fluorobenzaldehyde (8.00 g, 29.8 mmol) and dimethyl 3-aminobenzene-1,2-dicarboxylate (6.24 g, 29.8 mmol) in 10:1 MeOH-acetic acid (110 mL) was purged with nitrogen and treated with borane 2-picoline complex (4.78 g, 44.7 mmol). The reaction mixture was stirred at ambient temperature for 14 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH, and diluted with water (40 mL). The mixture was extracted with ethyl acetate (30 mL x 3) and the combined organic fractions were washed with saturated NaCl (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (5%-10% ethyl acetate in petroleum ether) to obtain 3-((4-(((third butyldimethylsilyl) as a yellow oil Oxy)methyl)-3-fluorobenzyl)amino) dimethyl phthalate (6.30 g, 45.8% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.33 (t, J = 7.7 Hz, 1H), 7.13-7.09 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 10.7 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 4.66 (s, 2H), 4.31 (d, J = 5.6 Hz, 2H), 3.75 (d, J = 7.7 Hz, 6H), 0.83 (s, 9H), 0.02 (s, 6H).

3-((3- fluoro- 4-( hydroxymethyl ) benzyl ) amino ) phthalic acid : To 3-((4-(((third butyldimethylsilyl)oxy)methyl Base)-3-fluorobenzyl)amino) dimethyl phthalate (13.3 g, 28.8 mmol) in a solution of 2:2:1 water-THF-MeOH (100 mL) was added sodium hydroxide ( 9.21 g, 230 mmol), and the reaction mixture was stirred at ambient temperature for 4 hours. The mixture was cooled to 0° C. and 6 M aqueous hydrochloric acid solution was added until pH=10. The mixture was concentrated to remove MeOH and THF and the residual aqueous mixture was cooled to 0°C. Subsequently, 6 M hydrochloric acid was added until pH=5 and the resulting precipitate was collected by filtration, washed with H ₂ O and dried in vacuo to give 3-((3-fluoro-4-(hydroxymethyl)benzyl as a yellow solid Group) amino group) phthalic acid (8.90 g, 96.8% yield). LCMS (ESI) m/z: 320.0 [M+1]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.99 (br s, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 11.2 Hz, 1H), 6.75 (d, J = 7.1 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 5.21 (s, 1H) , 4.50 (s, 2H), 4.44 (s, 2H).

2-(2,6-bi- pendant piperidin- 3 -yl )-4-((3- fluoro- 4-( hydroxymethyl ) benzyl ) amino ) isoindolin- 1,3 -di Ketone : To a solution of 3-aminopiperidine-2,6-dione hydrochloride (6.88 g, 41.8 mmol) in pyridine (20 mL), add 3-((3-fluoro-4-(hydroxymethyl Group) benzyl)amino group) phthalic acid (8.90 g, 27.9 mmol) and the mixture was stirred at 120° C. for 5 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL) and the solution was washed with 0.5 M HCl (300 mL), dried over MgSO ₄ and concentrated. The residual solid was dried in vacuo to give 2-(2,6-bi-sideoxypiperidin-3-yl)-4-((3-fluoro-4-(hydroxymethyl)benzyl)amino as a yellow solid ) Isoindoline-1,3-dione (9.00 g, 78.5% yield). LCMS (ESI) m/z: 394.0 [MH-18]+. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.11 (s, 1H), 7.51 (dd, J = 7.2, 8.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.29 (br s , 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 10.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H ), 5.08 (dd, J = 5.4, 12.9 Hz, 1H), 4.56 (br d, J = 5.4 Hz, 2H), 4.50 (s, 2H), 2.93-2.88 (m, 1H), 2.65-2.54 (m , 2H), 2.10-2.05 (m, 1H).

4-((4-( chloromethyl )-3- fluorobenzyl ) amino )-2-(2,6-bi- pendant piperidin- 3 -yl ) isoindoline- 1,3 -di Ketone : 2-(2,6-bi- pendant piperidin-3-yl)-4-((3-fluoro-4-(hydroxymethyl)benzyl)amino)isoindolin-1, A mixture of 3-diketone (4.00 g, 9.72 mmol) in dichloromethane (120 mL) was cooled to 0 °C and sulfenyl chloride (12.0 mL, 165 mmol) was added. The cooling bath was removed and the mixture was stirred at ambient temperature for 22 hours. The reaction mixture was poured into a mixture of ethyl acetate (400 mL) and saturated aqueous sodium bicarbonate solution (300 mL), which was mixed and the organic layer was removed. The aqueous layer was treated with saturated sodium bicarbonate to pH=5 and extracted with dichloromethane (300 mL x 3). All organic fractions were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (1:2:8 followed by 1:1:5 ethyl acetate/petroleum ether/dichloromethane) to provide 4-((4-(chloromethyl Yl)-3-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (3.24 g, 77.6% yield ). LCMS (ESI) m/z: 430.1 [M+1]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.12 (s, 1H), 7.50 (q, J = 8.1 Hz, 2H), 7.33 (br t, J = 6.3 Hz, 1H), 7.29-7.18 ( m, 2H), 7.04 (d, J = 7.0 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 5.08 (dd, J = 5.3, 12.9 Hz, 1H), 4.75 (s, 2H), 4.59 (br d, J = 6.2 Hz, 2H), 2.97-2.82 (m, 1H), 2.69-2.53 (m, 2H), 2.13-1.98 (m, 1H).

2-(2,6-bi- pendant piperidin- 3 -yl )-4-((3- fluoro -4-((4- isopropylpiperidin- 1 -yl ) methyl ) benzyl ) amine Group ) Isoindoline- 1,3 -dione : 4-((4-(chloromethyl)-3-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidine -3-yl)isoindoline-1,3-dione (0.060 g, 0.140 mmol) and 4-isopropylpiperidine hydrochloride (0.023 mg, 0.140 mmol) in anhydrous DMF (1.0 mL) DIEA (0.073 mL, 0.419 mmol) was added to the solution and the reaction mixture was stirred at 80°C for 15 hours. The reaction mixture was cooled to ambient temperature and quenched with 10% formic acid in DMSO (1.0 mL). The mixture was filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified by standard methods to give 2-(2,6-bi-sideoxypiperidin-3-yl)-4-((3-fluoro-4-( (4-isopropylpiperidin-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione (56.0 mg, 77% yield). LCMS (ESI) m/z 521.2 [M+H] ⁺ . Example 25 : 4-((4-((2,2 -dimethyl- 1 -oxa -8 -azaspiro [4.5] decane- 8- yl ) methyl )-3- fluorobenzyl ) amine Yl )-2-(2,6 -dipentoxypiperidin- 3 -yl ) isoindoline- 1,3 -dione

To 4-((4-(chloromethyl)-3-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3- A solution of dione (73.0 mg, 0.170 mmol) and 2,2-dimethyl-1-oxa-8-azaspiro[4.5]decane (37.4 mg, 0.221 mmol) in anhydrous DMSO (0.7 mL) DIEA (89.0 µL, 0.510 mmol) was added and the mixture was stirred at 50°C for 5 hours. The mixture was cooled to ambient temperature, diluted with 20% formic acid in DMSO (1 mL) and filtered through a membrane syringe filter (0.45 μm nylon). The solution was purified using standard methods to provide 4-((4-((2,2-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl)-3- Fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (36.0 mg, 37.7%). LCMS (ESI) m/z 563.2 [M+H] ⁺ . Example 26: (S) -6- (4- (4 - (((2- (2,6- two-oxo-piperidin-3-yl) -1,3-isoindoline-oxo - 4- yl ) amino ) methyl )-3- fluorobenzyl ) piperazin- 1 -yl ) nicotinamide

(S)-2-(2,6- Di- pendant piperidin- 3 -yl )-4-((2- fluoro- 4-( hydroxymethyl ) benzyl ) amino ) isoindolin- 1 ,3- Diketone : (S)-4-amino-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3-dione (5.00 g, 18.3 mmol) and 2-fluoro-4-(hydroxymethyl)benzaldehyde (2.82 g, 18.30 mmol) in 2:1 dioxane-MeOH (75 mL). The suspension was cooled to 0°C and a small portion was taken over 5 minutes B ₁₀ H ₁₄ (4.92 g, 40.3 mmol) was added. Equip the reaction flask with a septum and pinhole (pressure) and stir vigorously for 10 minutes. The mixture was brought to ambient temperature and stirred for 3 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (0-10% MeOH-DCM) to provide (S)-2-(2,6-di- pendoxypiperidin-3-yl) as a yellow solid )-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (4.23 g, 56%). LCMS (ESI) m/z 411.8 [M+H] ⁺ .

(S)-4-((4-( chloromethyl )-2- fluorobenzyl ) amino )-2-(2,6-bi- pendant piperidin- 3 -yl ) isoindoline- 1 ,3- Dione : (S)-2-(2,6-bi- pendant piperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino ) A solution of isoindoline-1,3-dione (0.727 g, 1.77 mmol) in anhydrous NMP (6 mL) was cooled to 0°C and methanesulfonyl chloride (0.275 mL, 3.35 mmol) and DIEA ( 0.617 mL, 3.35 mmol). The reaction mixture was brought to ambient temperature and stirred for 18 hours. The reaction mixture was slowly added to H ₂ O (60 mL), cooled to 0 °C while mixing vigorously. The resulting suspension was filtered, and the collected solid was washed with H ₂ O and Et ₂ O. The solid was dissolved in EtOAc and the solution was dried with MgSO ₄ , filtered and concentrated to provide (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino) as a yellow solid -2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (0.600 g, 79%). LCMS (ESI) m/z 430.0 [M+H] ⁺ .

(S)-6-(4-(4-(((2-(2,6- Di-pentoxypiperidin- 3 -yl )-1,3 -di- pendant isoindolin- 4 -yl ) Amino ) methyl )-3- fluorobenzyl ) piperazin- 1 -yl ) nicotinamide: to (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino )-2-(2,6-Dipentoxypiperidin-3-yl)isoindoline-1,3-dione (300 mg, 0.698 mmol) in anhydrous DMSO (1.0 mL) was added 6-(piperazin-1-yl) nicotinamide (144 mg, 1.00 mmol) and DIEA (0.122 mL, 0.698 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and diluted with DMSO (1 mL). By purifying the solution by palm-phase reverse-phase chromatography, (S)-6-(4-(4-(((2-(2,6-dipentoxypiperidin-3-yl)-1, 3-di- pendant isoindolin-4-yl)amino)methyl)-3-fluorobenzyl)piperazin-1-yl)nicotinamide (173 mg, 41%, >99% ee) , LCMS (ESI) m/z 600.2 [M+H] ⁺ . Example 27: (R) -6- (4- (4 - (((2- (2,6- two-oxo-piperidin-3-yl) -1,3-isoindoline-oxo - 4- yl ) amino ) methyl )-3- fluorobenzyl ) piperazin- 1 -yl ) nicotinamide

The palmar reverse phase chromatography described in Example 26 additionally provides (R)-6-(4-(4-(((2-(2,6-di-pentoxypiperidin-3-yl)- 1,3-bi- pendant isoindolin-4-yl)amino)methyl)-3-fluorobenzyl)piperazin-1-yl)nicotinamide (3 mg, >99% ee), LCMS (ESI) m/z 600.2 [M+H] ⁺ . Example 28 : 4-((4-((4-( T-butyl ) piperidin- 1 -yl ) methyl )-3- fluorobenzyl ) amino )-2-(2,6 -dioxy Piperidin- 3 -yl ) isoindoline- 1,3 -dione

To 4-((4-(chloromethyl)-3-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3- DIEA (0.10 mL, 0.573 mmol) was added to a solution of dione (0.050 g, 0.116 mmol) and 4-(third butyl) piperidine hydrochloride (0.025 mg, 0.141 mmol) in anhydrous DMF (1.0 mL). And the reaction mixture was stirred at 60°C for 3 hours. The reaction was cooled to ambient temperature and quenched with 10% formic acid in DMSO (1.0 mL). The mixture was filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified by standard methods to give 2-(2,6-bi-sideoxypiperidin-3-yl)-4-((3-fluoro-4-( (4-isopropylpiperidin-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione (49.0 mg, 78%). LCMS (ESI) m/z 535.2 [M+H]+. Example 29 : 4-(1-(4-(((2-(2,6- Di-sideoxypiperidin- 3 -yl )-1,3 -bi-sideoxyisoindolin- 4 -yl ) Amino ) methyl )-3 -methylbenzyl ) azetidin- 3 -yl ) benzonitrile

(4- Bromo- 3 -methyl - phenyl ) methanol : a solution of 4-bromo-3-methyl-benzoic acid (50.0 g, 232 mmol) in THF (500 mL) was cooled to 0°C and under nitrogen Borane dimethyl sulfide complex (35.0 mL, 350 mmol, 10 M in THF) was added next. The reaction mixture was brought to ambient temperature and stirred for 2 hours, followed by stirring at 40°C for 3 hours. The mixture was cooled to 0 °C and quenched with water (200 mL). The mixture was extracted with ethyl acetate (300 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give (4-bromo-3-methyl-phenyl)methanol (45.0 g, 96.3) as a brown oil %Yield). ¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 7.51 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.05 (dd, J = 1.6, 8.2 Hz, 1H), 4.63 (s, 2H), 2.41 (s, 3H).

(4-bromo-3-methyl-phenyl) - methoxy - tertiary butyl - dimethyl - Silane: a solution of (4-bromo-3-methyl-phenyl) - methanol (45.0 g, 224 mmol) (500 mL) was added sequentially a solution of the imidazole (38.1 g, 559 mmol) in dichloromethane and tert-butyl dimethyl silicone alkyl chloride (40.5 g, 269 mmol) and the reaction mixture was stirred at ambient temperature for 15 hour. The mixture was washed with water (2 x 500 mL), saturated NaCl (500 mL) and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated to give a brown oil of (4-bromo-3-methyl-phenyl) - methoxy - tertiary butyl - dimethyl - Silane (68.0 g, 96.4% yield ). ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.48 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 1.1 Hz, 1H), 7.02 (dd, J = 1.6, 8.1 Hz, 1H), 4.67 (s, 2H), 2.40 (s, 3H), 0.95 (s, 9H), 0.11 (s, 6H).

4 - [[tert-butyl (dimethyl) silicone alkyl] oxymethyl] -2-methyl - benzaldehyde: Under a nitrogen atmosphere, (4-bromo-3-methyl-phenyl) - methyl A solution of oxy-tert-butyl-dimethyl-silane (63.0 g, 200 mmol) in THF (600 mL) was cooled to -78°C and n-butyllithium (95.9 mL, 240 mmol, hexane) was added dropwise 2.5 M in alkane). The mixture was stirred at -78 °C for 2 hours and DMF (23.1 mL, 300 mmol) was added dropwise. The mixture was stirred at -78°C for 30 minutes, allowed to reach ambient temperature and stirred for 1 hour. The mixture was quenched with saturated ammonium chloride (300 mL), and extracted with ethyl acetate (300 mL). The organic phase was washed with saturated NaCl (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residual oil was purified by silica gel column chromatography (petroleum ether) to obtain 4-[[ third butyl(dimethyl)silyl]oxymethyl]-2-methyl as a brown oil -Benzaldehyde (45.0 g, 85.2% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 10.24 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 4.77 (s, 2H), 2.68 (s, 3H), 0.96 (s, 9H), 0.12 (s, 6H).

3-((4-((( T-butyldimethylsilyl ) oxy ) methyl )-2 -methylbenzyl ) amino ) dimethyl phthalate : To 4-[[ 第tributyl (dimethyl) silicone alkyl] oxymethyl] -2-methyl - benzaldehyde (20.0 g, 75.6 mmol) and 3-amino-1,2-dicarboxylate (15.0 g , 71.8 mmol) in MeOH (200 mL) was added acetic acid (20.0 mL, 350 mmol) and the mixture was stirred at ambient temperature for 6 hours. The mixture was cooled to 0 °C and borane 2-picoline complex (12.1 g, 113 mmol) was added in portions. The mixture was brought to ambient temperature and stirred for 15 hours. The mixture was concentrated and the residue was diluted with water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 0.5 M hydrochloric acid (300 mL), saturated NaCl (300 mL) and dried over anhydrous sodium sulfate. The dried solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give 3-((4-(((third Butyldimethylsilyl)oxy)methyl)-2-methylbenzyl)amino)dimethyl phthalate (18.0 g, 43.2% yield).

3-((4-( hydroxymethyl )-2 -methylbenzyl ) amino ) phthalic acid: 3-((4-(((third butyldimethylsilyl)oxy) Methyl)-2-methylbenzyl)amino) dimethyl phthalate (18.0 g, 32.7 mmol) in 1:1 THF-MeOH (200 mL) was added to water (50 mL) Sodium hydroxide (131 g, 327 mmol) and the mixture was stirred at ambient temperature for 15 hours. The mixture was concentrated to remove MeOH and THF, and the remaining aqueous mixture was cooled to 0°C. Then 6M hydrochloric acid was added until pH=7 and the resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 3-((4-(hydroxymethyl)-2-methylbenzyl)amino group as a yellow solid ) Phthalic acid (5.30 g, 51.4% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (br t, J = 5.3 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.11 (s, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.38 (br d, J = 7.4 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 5.07 (br s, 1H ), 4.43 (br s, 2H), 4.19 (br d, J = 5.1 Hz, 2H), 2.31 (s, 3H).

2-(2,6-bi- pendant piperidin- 3 -yl )-4-((4-( hydroxymethyl )-2 -methylbenzyl ) amino ) isoindoline- 1,3- Diketone : To a solution of 3-((4-(hydroxymethyl)-2-methylbenzyl)amino)phthalic acid (5.30 g, 16.8 mmol) in pyridine (60 mL), add 3- Aminopiperidine-2,6-dione hydrochloride (4.15 g, 25.2 mmol) and the mixture was stirred at 120°C for 10 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (300 mL). The solution was washed with 0.5 M hydrochloric acid (300 mL), dried over sodium sulfate, filtered, and concentrated to give 2-(2,6-dipentoxypiperidin-3-yl)-4-(( 4-(hydroxymethyl)-2-methylbenzyl)amino)isoindoline-1,3-dione (4.80 g, 70.1% yield). ¹ H NMR ( 400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.52 (dd, J = 7.2, 8.4 Hz, 1H), 7.20-7.12 (m, 2H), 7.10-7.01 (m, 2H ), 6.98-6.87 (m, 2H), 5.06 (dd, J = 5.4, 12.9 Hz, 1H), 4.50 (br d, J = 5.5 Hz, 2H), 4.42 (s, 2H), 2.95-2.79 (m , 1H), 2.64-2.52 (m, 2H), 2.33 (s, 3H), 2.08-1.99 (m, 1H).

4-((4-( chloromethyl )-2 -methylbenzyl ) amino )-2-(2,6-bi- pendant piperidin- 3 -yl ) isoindoline- 1,3- Diketone : 2-(2,6-bi- pendant piperidin-3-yl)-4-((4-(hydroxymethyl)-2-methylbenzyl)amino)isoindoline- To a solution of 1,3-dione (9.10 g, 22.3 mmol) in dichloromethane (200 mL) was added thionyl chloride (32.4 mL, 447 mmol) and the mixture was stirred at ambient temperature for 15 hours. The mixture was diluted with dichloromethane (300 mL) and poured into saturated sodium bicarbonate (300 mL), cooled to 0°C and mixed. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was slurried in 1:1 dichloromethane-petroleum ether (20 mL) and the solid was collected by filtration. The collected solid was purified by silica gel column chromatography (1:1 petroleum ether-20%-100% ethyl acetate in dichloromethane) to give 4-((4-(chloromethyl )-2-methylbenzyl)amino)-2-(2,6-dipentoxypiperidin-3-yl)isoindoline-1,3-dione (7.40 g, 70.8% yield ). LCMS (ESI) m/z : 426.1 [M+1] ⁺ . ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 11.12 (m, 1H), 7.52 (dd, J = 7.3, 8.4 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J = 1.0 Hz, 2H), 7.07-7.01 (m, 2H), 6.90 (d, J = 8.5 Hz, 1H), 5.07 (dd, J = 5.5, 12.9 Hz, 1H), 4.69 (s, 2H), 4.53 (d, J = 6.0 Hz, 2H), 2.94-2.79 (m, 1H), 2.64-2.52 (m, 2H), 2.34 (s, 3H), 2.09-2.00 (m, 1H).

4-(1-(4-(((2-(2,6- Di-Penoxypiperidin- 3 -yl )-1,3 -Di-Penoxyisoindolin- 4 -yl ) amino ) Methyl )-3 -methylbenzyl ) azetidin- 3 -yl ) benzonitrile : To 4-((4-(chloromethyl)-2-methylbenzyl)amino)-2 -(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3-dione (0.060 g, 0.141 mmol) and 4-(azetidin-3-yl)benzene To a mixture of nitrile hydrochloride (0.027 mg, 0.141 mmol) in anhydrous DMF (1.0 mL), DIEA (0.074 mL, 0.423 mmol) was added and the reaction mixture was stirred at 80°C for 15 hours. The reaction was cooled to ambient temperature and quenched with 10% formic acid in DMSO (1.0 mL). The mixture was filtered through a membrane syringe filter (0.45 μm nylon) and the leached solution was purified by standard methods to give 2-(2,6-bi- pendoxypiperidin-3-yl)-4-((3-fluoro -4-((4-isopropylpiperidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (49.0 mg, 59.9% yield). LCMS (ESI) m/z 548.2 [M+H] ⁺ . Example 30 : 4-((4-((4-( T-butyl ) piperidin- 1 -yl ) methyl )-2 -methylbenzyl ) amino )-2-(2,6 -side Oxypiperidin- 3 -yl ) isoindoline- 1,3 -dione

4-((4-(chloromethyl)-2-methylbenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3 -A solution of dione (0.050 g, 0.117 mmol), 4-(third butyl) piperidine (0.0249 mL, 0.176 mmol), and DIEA (0.102 mL, 0.585 mmol) in DMF (0.500 mL) at 60°C Stir under N ₂ atmosphere for 3 hours. The reaction was quenched with 10% formic acid in DMSO (1.0 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 4-((4-((4-(third butyl Yl)piperidin-1-yl)methyl)-2-methylbenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3 -Diketone (43.0 mg, 69.0%). LCMS (ESI) m/z 531.3 [M+H] ⁺ . Example 31 : 4-((4-((4-(2,4 -difluorophenyl ) piperazin- 1 -yl ) methyl )-2 -methylbenzyl ) amino )-2-(2, 6 -bi- pendant piperidin- 3 -yl ) isoindoline- 1,3 -dione

4-((4-(chloromethyl)-2-methylbenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3 -Diketone (0.060 g, 0.141 mmol), 1-(2,4-difluorophenyl)piperazine (0.031 g, 0.155 mmol), and DIEA (0.074 mL, 1.73 mmol) in DMF (1.00 mL) The solution was stirred at 80°C under N ₂ atmosphere for 15 hours. The reaction was quenched with 10% formic acid in DMSO (1.0 mL), filtered through a membrane syringe filter (0.45 μm nylon) and the solution was purified using standard methods to give 4-((4-((4-(2,4 -Difluorophenyl)piperazin-1-yl)methyl)-2-methylbenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline -1,3-dione (34.0 mg, 40.9%). LCMS (ESI) m/z 588.2 [M+H] ⁺ . Example 32 : (S)-2-(2,6- Di- pendant piperidin- 3 -yl )-4-((2- fluoro -4-((3- morpholinylazetidine- 1 - yl) methyl) benzyl) amino) isoindoline-1,3-dione

To (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline- 1,3-Dione (300 mg, 0.698 mmol) in anhydrous DMSO (1.0 mL) was added 4-(azetidin-3-yl)morpholine hydrochloride (125 mg, 0.698 mmol) And DIEA (0.122 mL, 0.698 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and diluted with DMSO (1 mL). By purifying the solution by palm-phase reverse phase chromatography, (S)-2-(2,6-di- pendantoxypiperidin-3-yl)-4-((2-fluoro-4-((3 -Morpholinylazetidin-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione (89 mg, 24%, 97% ee) LCMS (ESI) m /z 536.2 [M+H] ⁺ . Example 33 : (R)-2-(2,6- Di-Penoxypiperidin- 3 -yl )-4-((2- fluoro -4-((3- morpholinylazetidine- 1 - yl) methyl) benzyl) amino) isoindoline-1,3-dione

The palmar reverse phase chromatography described in Example 32 additionally provided (R)-2-(2,6-bi- pendantoxypiperidin-3-yl)-4-((2-fluoro-4-( (3-morpholinylazetidin-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione (16 mg, 97% ee) LCMS (ESI) m/ z 535.6 [M+H] ⁺ . Example 34: (S) -5- (4- (4 - (((2- (2,6- two-oxo-piperidin-3-yl) -1,3-isoindoline-oxo - 4- yl ) amino ) methyl ) benzyl ) piperazin- 1 -yl ) pyridinamide

To (S)-4-((4-(chloromethyl)benzyl)amino)-2-(2,6-bi- pendant piperidin-3-yl)isoindoline-1,3- To a solution of dione (300 mg, 0.619 mmol) in anhydrous DMSO (3.0 mL) was added 5-(piperazin-1-yl)pyridinecarboxamide (153 mg, 0.743 mmol) and DIEA (0.108 mL, 0.619 mmol ) And the mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with 15% formic acid in DMSO (3 mL) and the solution was purified by reverse phase chromatography to give (S)-5-(4-(4-(((2-(2,6-side Oxypiperidin-3-yl)-1,3-bi- pendant isoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)pyridinamide (255 mg , 71%, 95% ee), LCMS (ESI) m/z 582.2 [M+H] ⁺ . Example 35 : ((R)-5-(4-(4-(((2-(2,6- Di- pendoxypiperidin- 3 -yl )-1,3 -di- pendoxyisoindoline -4 -yl ) amino ) methyl ) benzyl ) piperazin- 1 -yl ) pyridinamide

By purifying the solution obtained in Example 34 or the racemic material obtained in Example 7 by palm chromatography, ((R)-5-(4-(4-(((2-(2,6-di Pendant piperidin-3-yl)-1,3-di pendant isoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)pyridinamide, LCMS (ESI) m/z 582.2 [M+H] ⁺ . Analysis based on cell analysis

SU-DHL-4 cell proliferation analysis. The following can be used to determine the isoindoline dione compound in DLBCL cell lines, such as SU-DHL-4 cell line (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ]: catalog number ACC-495) 120 hours after treatment Examples of analysis of anti-proliferative activity. The inoculation density of SU-DHL-4 can be optimized to ensure the linearity of analysis in 1536 well plates.

Take increasing concentrations of test compounds (0.5 nM to 10 μM) using an acoustic dispenser (EDC ATS-100), and point to an empty 1536-well plate at a 20-point dilution (unevenly spaced data points) in. The DMSO concentration is kept constant at 0.1% DMSO final analysis concentration. Before testing, SU-DHL-4 cells were grown in RPMI-1640 (Roswell Park Memorial Institute – 1640) medium containing 10% FBS (fetal bovine serum: HyClone) and expanded in culture flasks to provide a sufficient amount of Starting material. Cells were then diluted to 500 cells per well in a 5 µL volume and added directly to the 1536-well plate spotted with compound. The cells were grown in 5% CO ₂ at 37°C for 120 hours. At the beginning (t ₀ ) of the cells exposed to the compound, Cell Titer-Glo ^® fluorescent cell viability assay was used at a volume to volume ratio of 1 to 2: according to the manufacturer’s instructions (Promega Corporation, Madison, WI), by quantitative activity The fluorescence produced by the adenosine-5'-triphosphate (ATP) present in the cells was analyzed for the initial viable cell number. After 120 hours, Cell Titer-Glo ^{® was used to} analyze the cell viability of the treated cells and read the fluorescence. Activity Base (IDBS, Alameda, CA) was used to process and evaluate all growth inhibition curves. Using a four parameter logistic model (S-shaped dose - response model) based on cell viability IC ₅₀ values: y = (A + (( BA) / (1 + ((C / x) ^ D)))) where: A = Y _Min B = Y _Max C = EC ₅₀ D = Hill slope IC ₅₀ = compound concentration when Y = 50% of the DMSO control group Y = cell viability measured in fluorescent units, and x = compound concentration. In vivo analysis

WSU-DLCL2 (GCB- subtype ) triple blow (Myc , Bcl2 , Bcl6 rearrangement ) DLBCL xenograft model . WSU-DLCL2 cells are derived from a type of non-Hodgkin's lymphoma, namely diffuse large B-cell lymphoma. Female SCID mice (Fox Chase SCID®, CB17/Icr- Prkdcscid , Charles River) are characterized by severe combined T-cell and B-cell immunodeficiency. These mice are 10 weeks old and weighed on the first day of the study The range is from 15.4 to 24.2 g. With 10 x 10 ⁶ th WSU-DLCL2 cells were inoculated subcutaneously into female CB17 SCID mice of the abdominal flank. At the beginning of treatment, the mice were randomly divided into multiple treatment groups (n = 9/group), and treatment was started when the tumor was about 350 mm ³ on day 18. The test compound is administered once daily (QD) (at four dose levels). MCT administered with QD (0.5% methylcellulose, 0.25% Tween 80 and 50 mM citrate pH in PBS) was used as vehicle control. CHOP therapy caused by significant weight loss (cyclophosphamide (single dose on day 1), doxorubicin (single dose on day 1), vincristine (single dose on day 1), and prednisone ( A single cycle of combination QDx5) on days 1-5 was used as a positive control. The two endpoints in this study included tumor volume reduction (TVR) and time to progression (TTP). The TVR was judged at the end time point when the vehicle group reached the predetermined end point of about 1400 mm ³ . A tumor-free animal is defined as an animal with no palpable tumors or tumors <50 mm ³ . The TTP of the 30 mg/kg QD-treated group was followed to determine the tumor growth delay (TGD), which was defined as the difference in the number of days that the treated group's tumor reached a specified volume of 1000 mm ³ relative to the control group's tumor. Multiple dosing schedules can be tested. When the average tumor volume of the vehicle group reached the predetermined end point of about 1400 mm ³ , the final tumor volume reduction was determined at the end of the study.

SU-DHL-6 (GCB subtype ) double blow DLBCL xenograft model. SU-DHL-6 cells are derived from a type of non-Hodgkin's lymphoma, namely diffuse large B-cell lymphoma. The SU-DHL-6 cell line is a GCB type "double hit" (a combination of Myc and Bcl2 rearrangement) DLBCL. Female SCID mice (Fox Chase SCID®, CB17/Icr- Prkdcscid , Charles River) are characterized by severe combined T cell and B cell immunodeficiency. These mice are 10 weeks old. On the first day of this study, The weight range is from 15.4 to 24.2 g. With 10 x 10 ⁶ th SU-DHL-6 cells were inoculated subcutaneously into female CB17 SCID mice of the abdominal flank. At the beginning of treatment, the mice were randomly divided into multiple treatment groups (n = 7/group), and treatment was started when the tumor was about 170 mm ³ on day 28. On the 49th day, three weeks of oral administration were completed. When the average tumor volume of the vehicle group reached the predetermined end point of about 1400 mm ³ , the final tumor volume reduction was determined at the end of the study. MCT administered with QD (0.5% methylcellulose, 0.25% Tween 80, and 50 mM citrate pH in PBS) was used as a vehicle control group. R-CHOP therapy that will cause significant weight loss (rituximab (single dose on day 1), cyclophosphamide (single dose on day 1), doxorubicin (single dose on day 1), A single cycle of vincristine (single dose on day 1) and prednisone (QDx5 on days 1-5) was used as a positive control in a single cycle. The endpoint of this study included tumor volume reduction (TVR). The TVR was judged at the end time point when the vehicle group reached the predetermined end point of about 1400 mm ³ . A tumor-free animal is defined as an animal with no palpable tumors or tumors <50 mm ³ .

OCI-LY10 (ABC subtype ) DLBCL xenograft model. OCI-LY10 cells are derived from a type of non-Hodgkin's lymphoma, namely diffuse large B-cell lymphoma. Female SCID mice (Fox Chase SCID®, CB17/Icr- Prkdcscid , Charles River) are characterized by severe combined T cell and B cell immunodeficiency. These mice are 10 weeks old. On the first day of this study, The weight range is from 15.4 to 24.2 g. With 10 x 10 ⁶ th OCI-LY10 cells were inoculated subcutaneously into female CB17 SCID mice of the abdominal flank. At the beginning of treatment, mice were randomly divided into multiple treatment groups (n = 9/group), and treatment was started when the tumor was about 100 mm ³ on day 9. When the average tumor volume in the vehicle group reached a predetermined endpoint of about 1400 mm ³ , the final tumor volume reduction was determined at the end of the study. Rituximab (at a dose level administered intraperitoneally and administered once every two weeks) was used as a positive control. The endpoint of this study included tumor volume reduction (TVR). The TVR was judged at the end time point when the vehicle group reached the predetermined end point of about 1400 mm ³ . A tumor-free animal is defined as an animal with no palpable tumors or tumors <50 mm ³ .

Cell lines that can be used in the xenograft analysis described herein include GCB DLBCL cell lines (eg, Karpas-422, WSU-DLBCL2, SU-DHL-1, SU-DHL-4, SU-DHL-5, SU-DHL -6, SU-DHL-8, SU-DHL-10, HT, Farage, Pfeifer, or OCI-Ly7), ABC DLBCL cell line (e.g., OCI-Ly10, U2932, OCI-Ly3, or RC-K8), Or DHIT (double hit, ie cMyc and Bcl-2 mutant) or THIT (triple hit, ie Myc, Bcl2, Bcl6 rearrangement) cell line.

Isoindoline dione compounds have been or will be tested in DLBCL xenograft models, and have or will be shown to be effective as DLBCL treatment in the model. Activity table

The various isoindoline dione compounds in Table 1 were tested in one or more DLBCL cell proliferation assays, such as SU-DHL-4 cell proliferation assays, and were found to be active in these assays, with all compounds in this assay Has an IC _{50 of} less than 1 μM, some compounds have an IC _{50 of} less than 200 nM (activity level D), some compounds have an IC ₅₀ of from 200 nM to 500 nM (activity level C), and some compounds have an IC ₅₀ It is from 501 nM to 750 nM (activity level B), and other compounds have IC ₅₀ (activity level A) from 751 nM to 1 μM. Table 1 .

Many references have been cited, and the disclosures of these references are incorporated by reference in their entirety.

The embodiments described above are intended to be exemplary only, and those skilled in the art will recognize or will be able to determine many equivalents of specified compounds, materials, and procedures using only routine experimentation. All such equivalents are considered to be within the scope of the present invention and covered by the scope of the appended patent application.

Claims (42)

A compound of formula (I):

, Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, wherein: Ring A is a non-aromatic heterocyclic group optionally substituted; each R is independently substituted or Unsubstituted C _1-3 alkyl, or halogen; and n is 0, 1, 2, 3, or 4. The compound according to claim 1, wherein the compound is a compound of formula (II):

, Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer. The compound according to claim 1, wherein the compound is a compound of formula (III):

, Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer. The compound according to claim 1, wherein the compound is a compound of formula (IV):

, Or a pharmaceutically acceptable salt, tautomer, or isotope. The compound according to claim 4, wherein the compound is a compound of formula (V):

, Or a pharmaceutically acceptable salt, tautomer, or isotope. The compound of claim 4, wherein the compound is of formula (VI):

, Or a pharmaceutically acceptable salt, tautomer, or isotope. The compound according to claim 1, wherein the compound is a compound of formula (VII):

, Or a pharmaceutically acceptable salt, tautomer, or isotope. The compound according to claim 7, wherein the compound is a compound of formula (VIII):

, Or a pharmaceutically acceptable salt, tautomer, or isotope. The compound according to claim 7, wherein the compound is a compound of formula (IX):

, Or a pharmaceutically acceptable salt, tautomer, or isotope. The compound according to any one of claims 1 to 9, wherein ring A is

Wherein R ^a is H and R ^b is a C _1-6 alkyl group, non-aromatic heterocyclic group, aryl, heteroaryl, O-, or aryl; or R ^a and R ^b form together with the carbon they are attached 3-6 member cycloalkyl or 4-6 member non-aromatic heterocyclic group; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally substituted by one or more halogen, C _{1 -3} alkyl, or CN substitution. The compound according to any one of claims 1 to 9, wherein ring A is

Where R ^c is H, halogen, OH, or (C _1-3 alkyl); and R ^d is optionally substituted (C _1-3 alkyl), OR ¹ , C(O)N(R ² ) ₂ , SO ₂ (C _1-4 alkyl), C _3-7 cycloalkyl, non-aromatic heterocyclic group, aryl group, heteroaryl group, or O-heteroaryl group; or R ^c and R ^d together with its The attached carbons together form a 3-6 member cycloalkyl or 4-6 member non-aromatic heterocyclic group; wherein R ¹ is H, optionally substituted C _1-6 alkyl, or optionally substituted- (C _0-3 alkyl)-(C _3-7 cycloalkyl); each R ^{2 is} independently H or C _1-6 alkyl; and wherein the alkyl, cycloalkyl, heterocyclyl, aryl , Or heteroaryl is optionally substituted with one or more halogen, C _1-3 alkyl, or CN. The compound according to any one of claims 1 to 9, wherein ring A is

Wherein R ^e is C _1-6 alkyl, SO ₂ (C _1-4 alkyl), - (C _0-3 alkyl) - (C _3-7 cycloalkyl), aryl, heteroaryl or CO -Aryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted. The compound according to any one of claims 1 to 9, wherein ring A is a non-aromatic heterocyclic group optionally substituted with the following: azetidine; piperidinyl; piperazinyl; morpholine Group; 5-azaspiro[2,3]hexyl; 2-azaspiro[3.3]heptyl; 2-oxa-6-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl Group; 5-oxa-2-azaspiro[3.4]octyl; 6-oxa-2-azaspiro[3.4]octyl; 2-azaspiro[3.5]nonyl; 7-oxa- 2-azaspiro[3.5]nonyl; octahydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl; 6-azaspiro [3.4] Octyl; 2-oxa-6-azaspiro[3.4]octyl; 6-azaspiro[2.5]octyl; 7-azaspiro[3.5]nonyl; 1-oxa-8 -Azaspiro[4.5]decyl; 2-oxa-8-azaspiro[4.5]decyl; 2,8-diazaspiro[4.5]dec-1-oneyl; 3-oxa-9 -Azaspiro[5.5]undecyl; 1,4-oxazoyl; 8-azabicyclo[3.2.1]octyl; and isoindolinyl. The compound according to claim 13, wherein ring A is substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, OR ¹ , CON(R ² ) ₂ , SO ₂ (C _{1- 4} alkyl), N(R ² )SO ₂ (C _1-4 alkyl), -(C _0-3 alkyl)-(C _3-7 cycloalkyl), (non-aromatic heterocyclic group), Aryl, heteroaryl, O-aryl, O-heteroaryl, and C(O)aryl; where the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted ; Where R ¹ is H, optionally substituted C _1-6 alkyl, or optionally substituted -(C _0-3 alkyl)-(C _3-7 cycloalkyl); and each R ^{2 is} independent Ground is H, or C _1-6 alkyl. The compound according to claim 13, wherein ring A is substituted with one or more substituents independently selected from the group consisting of: F, Cl, Br, CH ₃ , CH ₂ CH ₃ , n-propyl, isopropyl, n-butyl , Second butyl, isobutyl, third butyl, n-pentyl, isopentyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ CF ₃ , CH (CH ₃ )CF ₃ , CH ₂ CH ₂ CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , O-isopropyl, O-n-propyl, O-n-butyl, O-isobutyl, O- Third butyl, OCF ₃ , O-cyclopropyl, O-cyclobutyl, OCH ₂ -cyclopropyl, OCH ₂ -cyclobutyl, CONH ₂ , CONH(CH ₃ ), CON(CH ₃ ) ₂ , SO ₂ CH ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, CH ₂ -cyclopropyl, CH ₂ -cyclobutyl; (non-aromatic heterocyclic group), It is selected from: azetidinyl, pyrrolidinyl, pyrrolidinyl, isothiazolidinyl, isothiazolidine 1,1-dioxy, piperidinyl, piperazinyl, morpholinyl, 3- Oxa-8-azabicyclo[3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, where the heterocyclic group is independently selected by one or more Substituted from the substituents of CH ₃ , CH ₂ CH ₃ , or CF ₃ ; phenyl, O-phenyl, or C(O)-phenyl, where the phenyl is optionally selected from one or more of F, Cl, CH ₃ , CN, or CONH ₂ substituent substitution; heteroaryl, which is selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl , Pyrazinyl, pyridazinyl, pyrimidinyl, or benzisoxazolyl, wherein the heteroaryl group is optionally selected from one or more of F, Cl, CF ₃ , CN, CONH ₂ , CONH ( CH ₃ ) ₂ or CON(CH ₃ ) ₂ substituent substitution; O-pyridyl and O-pyrimidinyl. The compound of claim 13, wherein ring A is substituted with one or more substituents independently selected from the group consisting of F, CH ₃ , CH ₂ CH ₃ , isopropyl, third butyl, CH ₂ F, CF ₃ , CH(CH ₃ )CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , O-isopropyl, O-n-propyl, O-isobutyl, O-third butyl, OCF ₃ , O-ring Butyl, OCH ₂ -cyclopropyl, CON(CH ₃ ) ₂ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, CH ₂ -cyclopropyl; (non-aromatic Heterocyclic group) selected from pyrrolidinyl, pyrrolidinyl, isothiazolidine 1,1-dioxy, morpholinyl, 3-oxa-8-azabicyclo[3.2.1]octyl, Or 8-oxa-3-azabicyclo[3.2.1]octyl, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from CH ₃ ; phenyl, O-phenyl or C(O)-phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH ₃ , CN, or CONH ₂ ; heteroaryl, which is selected from pyrazolyl , Oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, or benzisoxazolyl, wherein the heteroaryl group is optionally selected from one or more independently F , Cl, CF ₃ , CN, CONH ₂ , CON(CH ₃ ) ₂ substituent substitution; O-pyridyl and O-pyrimidinyl. The compound according to claim 13, wherein ring A is azetidinyl substituted with one or more substituents independently selected from C _1-6 alkyl, (non-aromatic heterocyclic group), aryl , Heteroaryl, O-aryl, and O-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. The compound according to claim 13, wherein ring A is azetidine substituted with one or more substituents independently selected from the group consisting of: CH ₂ CH ₃ , n-propyl, isopropyl, n-butyl, Second butyl, isobutyl, third butyl; CF ₃ ; pyrrolidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl, which is optionally substituted with one or more CH ₃ ; 3-oxa-8-azabicyclo[3.2.1]octyl; 8-oxa-3-azabicyclo[3.2.1]octyl; pyrazolyl; 2-pyridyl; 3-pyridyl; 4-pyridyl, phenyl; and O-phenyl; wherein the phenyl is optionally substituted with one or more substituents selected from F or CN. The compound according to claim 13, wherein ring A is piperidinyl substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, OR ¹ , CON(R ² ) ₂ , SO ₂ (C _1-4 alkyl), C _3-7 cycloalkyl, non-aromatic heterocyclic group, aryl, heteroaryl, and O-heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic Radical, aryl, or heteroaryl is optionally substituted; where R ¹ is H, optionally substituted C _1-6 alkyl, or optionally substituted -(C _0-3 alkyl)-( C _3-7 cycloalkyl); and each R ^{2 is} independently H, or C _1-6 alkyl. The compound according to claim 13, wherein ring A is piperidinyl substituted with one or more substituents independently selected from the group consisting of: F, Cl, CH ₃ , CH ₂ CH ₃ , n-propyl, isopropyl, and n Butyl, second butyl, isobutyl, third butyl, CH ₂ F, CHF ₂ , CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , O-n-propyl, O-isopropyl, O -N-butyl, O-isobutyl, O-third butyl, OCF ₃ , O-cyclopropyl, O-cyclobutyl, OCH ₂ -cyclopropyl, OCH ₂ -cyclobutyl, CONH ₂ , CONH(CH ₃ ), CON(CH ₃ ) ₂ , SO ₂ CH ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, pyrrolidone, isothiazolidine 1, 1-dioxy, morpholinyl; tetrahydrofuranyl, tetrahydropiperanyl, pyrazolyl; oxadiazolyl, which is optionally substituted with CH ₃ ; phenyl, which is optionally substituted with one or more F; 2-pyridyl, 3-pyridyl, 4-pyridyl, O-2-pyridyl, O-3-pyridyl, and O-4-pyridyl. The compound according to claim 13, wherein ring A is piperidinyl substituted with one or more substituents independently selected from the group consisting of: F, CH ₃ , CH ₂ CH ₃ , isopropyl, third butyl, CHF ₂ , CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , O-isopropyl, O-isobutyl, O-third butyl, OCF ₃ , O-cyclobutyl, OCH ₂ -cyclopropyl, CON (CH ₃ ) ₂ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, pyrrolidone, isothiazolidine 1,1-dioxy, morpholinyl; tetrahydropiperanyl, Pyrazolyl, oxadiazolyl, which is substituted with CH ₃ ; phenyl, which is substituted with one or more F; 2-pyridyl, and O-2-pyridyl. The compound according to claim 13, wherein ring A is piperazinyl substituted with one or more substituents independently selected from C _1-6 alkyl, SO ₂ (C _1-4 alkyl), and -(C _0-3 alkyl)-(C _3-7 cycloalkyl), aryl, heteroaryl, and CO-aryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally via replace. The compound of claim 13, wherein ring A is piperazinyl substituted with one or more substituents independently selected from the group consisting of: CH ₃ , CH ₂ CH ₃ , n-propyl, isopropyl, n-butyl, and Dibutyl, isobutyl, tertiary butyl, CF ₃ , CH ₂ CF ₃ , CH(CH ₃ )CF ₃ , SO ₂ CH ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl Group, cyclobutyl, (CH ₂ )cyclopropyl, (CH ₂ )cyclobutyl; phenyl, which is optionally substituted by one or more Cl, F, CN, CH ₃ , CONH ₂ ; pyrazolyl, It is optionally substituted by CH ₃ or CH ₂ CH ₃ ; oxazolyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; oxadiazolyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; thiadiazole Oxazolyl, which is optionally substituted with CH ₃ , CH ₂ CH ₃ , or CF ₃ ; 2-pyridyl, 3-pyridyl, or 4-pyridyl, each of which is optionally Cl, F, CF ₃ , CN, CONH ₂ , CONH(CH ₃ ) or CON(CH ₃ ) ₂ ; pyrazinyl, which is optionally substituted by CH ₃ or CH ₂ CH ₃ ; pyrimidinyl, which is optionally substituted by OCH ₃ ; benzisoxazole Radical; and CO (phenyl), wherein the phenyl is optionally fluorinated. The compound according to claim 13, wherein ring A is piperazinyl substituted with one or more substituents independently selected from the group consisting of: CH ₃ , isopropyl, third butyl, CH(CH ₃ )CF ₃ , SO ₂ CH ₂ CH ₃ , SO ₂ -isopropyl, cyclopropyl, cyclobutyl, (CH ₂ )cyclopropyl; phenyl, which is optionally one or more Cl, F, CN, CH ₃ , CONH ₂ substituted; pyrazolyl, which is optionally substituted by CH ₃ ; oxazolyl, which is optionally substituted by CH ₃ ; oxadiazolyl, which is optionally substituted by CH ₂ CH ₃ ; thiadiazolyl, which is optionally Substituted by CH ₃ or CH ₂ CH ₃ ; 2-pyridyl, which is optionally substituted by Cl, F, CF ₃ , CN, or CONH ₂ ; 3-pyridyl, which is optionally substituted by CF ₃ , CN, CONH ₂ , Or CON(CH ₃ ) ₂ substitution; 4-pyridyl, which is optionally substituted with CONH ₂ ; pyrazinyl, which is optionally substituted with CH ₃ ; pyrimidinyl, which is optionally substituted with OCH ₃ ; benzisoxazole Radical; and CO (phenyl), wherein the phenyl is optionally fluorinated. The compound according to claim 13, wherein ring A is morpholinyl, R is F or CH ₃ , and n is 1. The compound according to claim 13, wherein ring A is selected from 5-azaspiro[2,3]hexyl; 2-azaspiro[3.3]heptyl; 2-oxa-6-azaspiro[3.3]heptan Group; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl; 6-oxa-2-azaspiro[3.4]octyl; 2-azaspiro [3.5] Nonyl; 7-oxa-2-azaspiro[3.5]nonyl; octahydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-hexahydrocyclopenta [c]pyrrolyl; 6-azaspiro[3.4]octyl; 2-oxa-6-azaspiro[3.4]octyl; 6-azaspiro[2.5]octyl; 7-azaspiro[ 3.5] Nonyl; 1-oxa-8-azaspiro[4.5]decyl; 2-oxa-8-azaspiro[4.5]decyl; 2,8-diazaspiro[4.5]dec- 1-keto; 3-oxa-9-azaspiro[5.5]undecyl; 1,4-oxazo; 8-azabicyclo[3.2.1]octyl; and isoindoline Radicals; each of which is optionally substituted with one or more CH ₃ or F. The compound according to any one of claims 1 to 26, wherein R is F. The compound according to any one of claims 1 to 26, wherein R is CH ₃ . The compound according to any one of claims 1 to 28, wherein n is 1. The compound according to claim 1, wherein the compound is selected from Table 1. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, and a pharmaceutically acceptable The carrier, excipient or vehicle. A method for treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering an effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutical composition according to claim 31 to an individual in need . The method of claim 32, wherein the DLBCL is relapsed or refractory DLBCL. The method according to claim 33, wherein the DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and One or more of etoposide, bendamustine, lenalidomide, or gemcitabine are refractory. The method of claim 32, wherein the DLBCL is a newly diagnosed DLBCL. The method of any one of claims 32 to 35, the method further comprising administering rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamus One or more of Ting, Lenalidomide, or Gemcitabine. A compound as claimed in any one of claims 1 to 30 or a pharmaceutical composition as claimed in 31, for use in a method for treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering to an individual in need thereof Amount of the compound or the pharmaceutical composition. The compound or pharmaceutical composition used in claim 37, wherein the DLBCL is relapsed or refractory DLBCL. The compound or pharmaceutical composition used in claim 38, wherein the DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine, People who are refractory to lenalidomide or one or more of gemcitabine. The compound or pharmaceutical composition used in claim 37, wherein the DLBCL is a newly diagnosed DLBCL. The compound or pharmaceutical composition used in any one of claims 37 to 40, further comprising administration of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide , One or more of bendamustine, lenalidomide, or gemcitabine. A method for preparing compound of formula (I):

The method includes making the compound of formula (Ia):

, versus

, In the presence of a base, in a solvent, under conditions suitable to provide the compound of formula (I), wherein ring A is a non-aromatic heterocyclic group optionally substituted; each R is independently substituted or unsubstituted Substituted C _1-3 alkyl, or halogen; n is 0, 1, 2, 3, or 4; and LG is OM, OT, or halogen.